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Primary hyperoxaluria type 1 : clinical, genetic and biochemical studies

van Woerden, C.S.

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Citation for published version (APA):van Woerden, C. S. (2008). Primary hyperoxaluria type 1 : clinical, genetic and biochemical studies.

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CHAPTER 01 GENERAL INTRODUCTION

Parts of this chapter have been published in

Nederlands Tijdschrift voor Geneeskunde 2006;150:1669-72

This thesis focuses on a single metabolic disorder of the liver, called primary hyperoxaluria type 1 (PH1; MIM 259900). It is characterisedby an overproduction of oxalate because of a deficiency of the peroxiso-mal enzyme alanine:glyoxylate aminotransferase. The clinical expres-sion and the molecular-biochemical characteristics of PH1 are extreme-ly heterogeneous. Patients may be asymptomatic, suffer from stone dise-ase, or develop end-stage renal disease and systemic oxalosis with multi-organ disease. Presentation occurs at any age. Until recently, severalimportant questions about PH1 were still unanswered:● Which patients are at risk for a severe course of the disease? ● What is the optimal therapeutic strategy in any particular patient? ● What is the exact source of glyoxylate, the direct precursor of oxalate? Aiming to find answers to these questions, we investigated the epidemi-ology of PH1 in The Netherlands. We also looked for associations betweenclinical characteristics and genetic and biochemical features in patients,in order to develop parameters that may facilitate the diagnostic proce-dures and decision-making in the treatment of patients with PH1. Inaddition, we investigated the incidence of hyperoxaluria in the Zellwegerspectrum disorders, which comprise a group of patients with a genera-lized loss of peroxisomal functions. Finally, we aimed to measure therate of appearance of oxalate in plasma in humans, and to unravel theexact sources of glyoxylate in order to find clues for new therapeuticapproaches.

This chapter presents an overview of primary hyperoxaluria type 1:01.01 the history of research in the twentieth century01.02 its classification01.03, 01.04

and 01.05 its metabolic and molecular basis 01.06 the pathophysiology and mechanisms leading to renal

involvement and symptoms01.07 a description of the clinical characteristics and outcome01.08

and 01.09 an overview of diagnosis and treatment01.10 an introduction to the Zellweger spectrum disorders01.11 a short description of secondary hyperoxaluria01.12 an outline of the research questions that we address in

this project.

The colour illustrations of Chapter 01 can be found on the cover.CHAPTER 01

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HISTORY OF PH1Renal calculi are one of the oldest reported medical problems inhumans, as demonstrated by archaeological studies and descriptionsby Hippocrates, Celsus, Galen and Morgagni (68). Oxalate was recogni-zed as a natural product in the eighteenth century. Already in the early19th century, it had become possible to analyse urine crystals, and cal-cium oxalate was recognised as a frequent element of kidney stones, asreviewed by Hockaday and associates in 1839 (73). A four-and-a-halfyear old boy with “infiltration of renal parenchyma with crystallinedepositions” was described in 1925 by Lepoutre (108), later marked asthe first published case with primary hyperoxaluria. Urinary oxalatecould not be measured at that time, but Lepoutre stated that this wasa human presentation of renal oxalate calcification. He compared hisfindings with the animal studies of Ebstein and Nicolaier in 1897 (53).These investigators were able to induce the formation of calcium oxa-late kidney stones in rabbits and dogs, following the administration ofoxalate and oxamid in drinking water. Until the 2nd half of the 20thcentury, sporadic cases of the same type of kidney crystal depositionwere published. One of the striking clinical stories tells about a boy, 11years of age in 1942, who received a physical examination and a urineexamination at the request of his mother, because of nocturia and poly-dypsia. It revealed extensive calcification of the renal parenchyma ofboth kidneys, called nephrocalcinosis, which appeared to involve themedullary pyramids predominantly, with some ureteral dilatation(212). In the early 1950s, two detailed reports appeared of childrenwho died at 7 and 12 years of age of renal insufficiency with systemicoxalate depositions in multiple tissues and organs. This was the firstclinical and pathological report of the most severe clinical form of pri-mary hyperoxaluria, called oxalosis (26,50). Adult patients with hyper-oxaluria and kidney stones were described as well. By 1960, Antoineand colleagues retrieved 36 cases in whom kidney parenchymal oxala-te depositions had been found (4,30). They reviewed all cases, andfound that presentation could be as early as 3 months of age up to aslate as 57 years of age. An inherited defect was suspected, on the basisof the reports of affected relatives and identical twins (5). The combi-nation of elevated levels of urinary oxalate with this clinical picture ofnephrocalcinosis was identified in 1953 and in 1957 (6). Followingurine analyses of patients, parents and controls using isotope-dilutiontechniques, elevated glycolate levels were demonstrated for the firsttime by Frederick et al. in 1963 (56). A second inherited form of hyper-oxaluria was recognized in 1968, with the coincidence of elevated uri-nary oxalate and L-glycerate instead of glycolate (208). Subsequent stu-dies led to the identification of the enzyme defect in PH2 at the levelof D-glycerate dehydrogenase, which also displays glyoxylate reducta-se activity. Speculations about the metabolism leading to the genera-tion of oxalate were already going on since the early 1950’s. Glyoxylate


became recognized as the direct precursor of oxalate and experimentsin the early 1960’s pointed towards a defect in the glyoxylate to glycineinterconversion in primary hyperoxaluria type 1 (56). However, it wouldtake more than 20 years until Danpure and co-workers were the first toidentify a deficient activity of the liver specific enzyme AGT(alanine:glyoxylate aminotransferase) in PH1 patients (47). Since then, anumber of case reports and some comprehensive epidemiologic studieshave been published (27, 72, 112). Insight into the origins of PH1 wasfurther advanced when the gene mutated in PH1 was identified in 1991which made DNA diagnosis possible (161). The biochemical and geneticcauses of PH2 were unravelled later (39, 174) and patients were descri-bed, although at a much lower frequency compared to PH1 (95, 207).

GENERAL CONCEPT AND CLASSIFICATION OF PRIMARY HYPEROXALURIAHyperoxaluria can be the result of a genetic metabolic defect, as in primary hyperoxaluria type 1 or type 2, leading to an excessive endo-genous oxalate production or can be caused by increased intestinaloxalate absorption, or decreased excretion, called secondary hyperoxa-luria (FIGURE 01.1). Urinary oxalate levels are generally higher in pri-mary hyperoxaluria, but the secondary form can lead to severe morbi-dity as well. Because of the clinical impact of hyperoxaluria in patientswith other disorders (e.g. disorders of the gastro-intestinal tract), anoverview of secondary hyperoxaluria is given at the end of this chapter.

Classification of hyperoxaluria. Two genetic metabolic types of primaryhyperoxaluria are known, and three ways of developing secondaryhyperoxaluria are distinguished

PH1Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inheriteddisorder of glyoxylate metabolism due to deficiency of a peroxisomalenzyme, named alanine:glyoxylate aminotransferase, AGT (47). Due to

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this deficiency, peroxisomal glyoxylate cannot be transaminated intoglycine, but is oxidized into oxalate and reduced into glycolate. A singlemutated gene, called the AGXT gene, mapped at chromosome 2q37.3, con-stitutes the molecular basis of the AGT enzyme deficiency (161).

In humans, oxalate is an end product of glyoxylate metabolism. Anyexcess of oxalate, either produced endogenously or by ingestion oflarge amounts of oxalate, is transported via the blood stream to thekidneys and subsequently excreted into the urine. Due to the very lowsolubility of the calcium salt of oxalate, the concentration process ofthe urine may lead to crystal formation in the urinary tract as well asin the renal parenchyma (FIGURE 01.2 and 01.3). Crystals are demon-strated by light microscopy in a kidney biopsy specimen, and can bemade visible especially using polarized light microscopy (FIGURE 01.4)or after von Kossa staining (FIGURE 01.5). Calcium oxalate cystallizationmay become visible as nephrocalcinosis or renal stones on ultrasoundor abdominal X-ray (FIGURES 01.6 and 01.7). The striking feature ofnephrocalcinosis is a diffusely increased echogenicity of the renalparenchyma at normal to low gain settings (116, 210). This abnormalpattern is evident when comparing the kidneys with adjacent liver tis-sue, which usually contains more internal echoes than the renal paren-chyma. More invasive diagnostic procedures may reveal calcium oxala-te crystals attached to tubular epithelium of nephrons (FIGURE 01.5).Calcifications can result in interstitial nephritis and fibrosis, eventual-ly leading to renal insufficiency and end-stage renal disease (ESRD).When renal insufficiency develops, calcium oxalate depositions notonly accumulate in renal parenchyma but also in other tissues. Theseextrarenal sequelae are called oxalosis or systemic oxalosis (21).

PH2Primary hyperoxaluria type 2 (PH2) is a disorder of glyoxylate but alsoof hydroxypyruvate metabolism (208). Mutations in the glyoxylatereductase/ hydroxypyruvate reductase gene, the GRHPR gene, result ina deficiency of the bifunctional enzyme glyoxylate reductase/ hydro-xypyruvate reductase, GR/HPR, with development of hyperoxaluria andhyper-L-glyceric aciduria (174) (FIGURE 01.8 presents the metabolicscheme). Excess oxalate gives rise to the same phenotype as found inPH1 albeit less severe, and with much less patients recognized so far.A further description of PH2 is beyond the scope of this thesis.

Unclassified PHIn six reports, a total number of 13 patients, some of them being sibpairs, with atypical PH leading to renal involvement (urolithiasis andnephrocalcinosis, declining renal function) have been described (38,98, 132, 134, 140, 193). Common to all patients, AGT and GR/HPR acti-vities were normal, AGT was normally localized in peroxisomes and

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DNA analysis of AGXT or GRHPR genes was unremarkable. Urine samp-les showed hyperoxaluria (six patients, of which one sib pair), hyper-glycolic aciduria (three patients of which one sib pair), or a combina-tion of the two (four patients). One report described a decline of uri-nary glycolate levels upon pyridoxine administration (98). It is sug-gested that glycolate oxidase (GO) may be involved in this disorder (seebelow) (134), but the exact nature of this type of primary hyperoxalu-ria has not been found yet.

PRIMARY HYPEROXALURIA: THE ORIGIN OF OXALATE Main precursors Oxalate, excreted in urine, is derived from both dietary sources andfrom endogenous synthesis. The dietary contribution used to be esti-mated at 10% of total urinary oxalate (7), but recent investigations haveshown that oxalate may be derived in approximately equal parts fromthe diet and endogenous liver metabolism. The dietary oxalate contri-bution may vary since oxalate absorption depends on calcium intake(76). Precursors of endogenous oxalate synthesis are sugars and aminoacids (171) of which glycine is the most closely related to oxalate (41).The only studies which investigated the biochemical pathways leadingto oxalate production report a 40% contribution of glycine to oxalatesynthesis (11, 41). Glyoxylate plays a pivotal role in the endogenousoxalate generation (169). Ascorbate is probably the only non-enzymiccontributor to the oxalate production, but its role seems insignificantin PH1 patients (11, 12, 14, 42), as studies that suggested an importantcontribution of ascorbate to urinary oxalate production may have beenbiased by the use of imprecise, analytical procedures for oxalate detec-tion. Moreover, ascorbic acid may be converted to oxalate after voidingof urine, thus overestimating endogenous oxalate synthesis.

Glyoxylate: its transamination, oxidation and reductionGlyoxylate can be transaminated into glycine (FIGURE 01.8). This con-version detoxifies the cell from the reactive aldehyde glyoxylate. It isonly this single conversion, which is catalyzed by the AGT enzyme,which deficiency leads to the appearance of primary hyperoxaluriatype 1. Apart from AGT, however, the more widely dispersed glutama-te:glyoxylate aminotransferase (GGT) has the same function, althoughlocalized in the cytosol. However, for human glyoxylate metabolism,which is mainly localized in liver peroxisomes, AGT is the most impor-tant enzyme (145). As common to many aminotransferases, pyridoxalphosphate is the cofactor of this enzyme (60, 188). Pyridoxal phospha-te is synthesized from pyridoxine, vitamin B6, and depletion of pyri-doxine has been associated with a rise in urinary oxalate excretion inanimal experiments (61). A human patient with hyperoxaluria due topyridoxine deficiency has never been observed, though. Apart fromtransamination, glyoxylate can also be oxidized to oxalate, or reduced

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to glycolate. Glycolate oxidase (GO) and lactate dehydrogenase (LDH)both catalyze glyoxylate oxidation (164). Of these enzymes, glycolateoxidase is exclusively expressed in peroxisomes, catalyzing the con-version of glyoxylate into oxalate. However, when abundant glyoxylateis present, LDH may catalyze the same reaction in the cytosol, onceexcess glyoxylate has passed into the cytosol (8). The cytosolic enzy-mes glyoxylate reductase (GR) (180, 208) and lactate dehydrogenase(LDH) reduce glyoxylate to glycolate (FIGURE 01.8) (180). In PH1, thesum of biochemical pathways involving glyoxylate metabolism yieldoxalate and glycolate, that are excreted in urine.

Biochemical pathways in primary hyperoxaluria type 1 and type 2. AGT; alanine:glyoxylate aminotransferase, GO; glycolate oxidase, DAO;D-amino acid oxidase, LDH; lactate dehydrogenase, GR/HPR; glyoxylatereductase/ hydroxypyruvate reductase

Glycine and Glycolate, precursors of Glyoxylate in peroxisomesTwo direct precursors of glyoxylate are glycine and glycolate. In liverperoxisomes, D-amino acid oxidase (DAO) catalyzes the conversion ofglycine to glyoxylate (FIGURE 01.8). Glycolate is oxidized by glycolateoxidase (GO) (219). Both DAO and GO are peroxisomal enzymes. A by-product in the oxidation reaction is H2O2, which is degraded in peroxis-omes by catalase.In contrast to the metabolism of glycine, which is well established, themetabolic origin of glycolate is much more obscure. At least underexperimental conditions, the following substrates have been proposedas precursors of glycolate: glycolaldehyde and ethylene glycol (32),

FIGURE 01.8.

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xylitol (58, 92), hydroxypyruvate, ethanolamine (170) and fructose (91,142, 171). Their exact contribution to glycolate and oxalate synthesisin humans is unknown. However, [14C1]hydroxypyruvate and[14C1]ethanolamine were studied and appear not to be effective pre-cursors of [14C]oxalate (59). For hydroxypyruvate, reduction to D-gly-cerate by glyoxylate/ hydroxypyruvate reductase, GR/HPR, is obser-ved, hence preventing glycolate generation in the cytosol (FIGURE 01.8).The importance of this reaction is illustrated by PH2, in which GR/HPRdeficiency results in the conversion of hydroxypyruvate into L-glyce-rate and oxalate (FIGURE 01.8). Clinical studies gave evidence for therole of ethylene glycol, xylitol and fructose as oxalate precursorsbecause patients who were intoxicated with these compounds devel-oped calcium oxalate kidney stones as well as renal insufficiency (66,90, 109, 126, 142, 222). Another pathway was proposed, in which gly-colate dehydrogenase converts glycolate directly to oxalate. This reac-tion was thought to bypass glyoxylate (FIGURE 01.9). However, no fur-ther evidence for such a route was found after analysis of rat liver frac-tions and human urine samples of LDH subunit deficient patients (217).

Xylitol, fructose, glycolate and glyoxylate metabolism, adapted from James et al (172), 3; aldehyde dehydrogenase, 4; glycolateoxidase, 5; glycolate oxidase and lactate dehydrogenase, 6; glycolatedehydrogenase, 7; hydroxypyruvate decarboxylase, 8; alanine:glyoxylateaminotransferase (synonym: serine:pyruvate aminotransferase).Note: Hypothetical conversion, is not widly believed to occur.

Hydroxyproline: a precursor of Glyoxylate in mitochondriaHydroxyproline, a break down product of collagen (153), is anothersource for glyoxylate formation. Its importance has been suggestedrecently (99, 100). Hydroxyproline is metabolized mainly in mitochon-

FIGURE 01.9

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dria of hepatocytes and renal proximal tubule cells. Its metabolic con-version results in the formation of equal amounts of pyruvate and gly-oxylate (99). Daily collagen turnover in humans, which is estimated at2-3g/day (153), leads to the generation of 240-420mg of hydroxyproli-ne and of 140-240mg of glyoxylate. Another source of hydroxyprolineis dietary consumption, especially by ingestion of collagen-containingmeat products and gelatine-containing foods. Human experimentsdemonstrating a rise in oxalate and glycolate excretion upon gelatineconsumption, support this notion (100).

ALANINE:GLYOXYLATE AMINOTRANSFERASE (AGT)AGT deficiency in human PH1The enzyme alanine:glyoxylate aminotransferase (AGT) is a liver speci-fic, peroxisomal enzyme which is deficient in PH1 patients, as firstdemonstrated by Danpure and colleagues (47). The immunocytochemi-cal localization was studied by Cooper et al. using protein A-goldimmunocytochemistry (33). AGT consists of 392 amino acid residuesand is encoded by a single gene, the AGXT gene. In PH1 patients AGT isdeficient in its activity, although in many patients a significant residu-al AGT activity, up to more than 50% of normal value, can be detected(33, 47). Different levels of immunoreactivity of the AGT protein werefound as well. No correlation between levels of residual activity on theone hand, and the severity of clinical signs and symptoms on the otherhand, could be detected (43, 48).

After its synthesis on free polyribosomes, AGT normally dimerizes andis imported into liver peroxisomes in humans. Dimerization is not aprerequisite per se for peroxisomal routing, but it prevents mitochon-drial import (137, 221). The peroxisomal import is facilitated by aperoxisomal targeting sequence Lys-Lys-Leu (KKL), localized at the C-terminus of the polypeptide (137). The KKL-sequence differs from theprototypical, well conserved PTS1 sequence Ser-Lys-Leu (SKL) which isusually found in peroxisomal enzymes. A specific region of humanAGT, called PTS1A, probably contains additional peroxisomal targetinginformation (86). Although the exact mechanism leading to a stableperoxisomal targeting signal is unclear, the PTS1A and PTS1 regioninteract closely in the three-dimensional crystal structure of AGT.Normally, human AGT is found exclusively in peroxisomes, but sur-prisingly, based on genetic evidence, 4 % of healthy humans is predic-ted to have a combination of 5% of mitochondrion targeted AGT and95% peroxisome targeted AGT in liver cells (162). This results from thecreation of a mitochondrial targeting signal at the N-terminus thatoverrules the peroxisomal targeting information.

These peculiarities in combination with their genetic background aredescribed below in the paragraph THE AGXT GENE.

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AGT crystal structureThe crystal structure of AGT has been unravelled recently, facilitatingpredictions regarding genotype and enzymatic phenotype (221). AGT isa homodimer, built from two identical subunits. Each monomer con-sists of a large N-terminal domain and a smaller C-terminal domain.The core of the dimerization interface is formed by two helices and fiveconnecting loops. This results in a surface, which is in close contactwith the same area of the other monomer. The pyridoxal phosphate co-factor binds in a pocket at the dimer interface, and facilitates the cata-lytic and enzymatic function of AGT.

Species differences in AGT intracellular localization In most humans, the localization of AGT is restricted to the peroxis-omes. Yet, in other vertebrates, like cats and dogs, AGT is predomi-nantly localized in mitochondria and only in a small proportion inperoxisomes. In other mammals, AGT is evenly distributed betweenboth peroxisomes and mitochondria, like in rats or marmosets. The subcellular localization of AGT is thought to have changed during evolu-tion, depending on the dietary contribution of oxalate in different spe-cies (45). For example, a vegetable diet, containing relatively highamounts of glycolate or oxalate, requires adequate break down of oxa-late precursors to obtain a minimal endogenous production of oxalate.For this reason it is thought that the AGT enzyme is localized inperoxisomes in herbivores such as sheep (45, 75). On the other hand,carnivores have a high intake of collagen, which is also a precursor ofoxalate via conversion into hydroxypyruvate and glyoxylate.Therefore, they require an adequate breakdown of collagen compo-nents. Since hydroxyproline metabolism has been localized in mito-chondria (99), the AGT localized in mitochondria is likely to detoxifyglyoxylate in this compartment. For humans, the expression of so cal-led polymorphic mitochondrion targeted AGT (paragraph THE AGXT

GENE) occurs more frequently in areas where meat is an important die-tary component in contrast to areas where vegetables are the mostcommon dietary component .

THE AGXT GENECloning and mappingThe AGXT gene encoding the AGT enzyme (161), consists of 11 exons,ranging from 64 to 407 base pairs, and spans about 10 kb at the telom-eric end of the long arm of chromosome 2, 2q37.3. It is composed of 11exons. The open reading frame encodes a polypeptide of 392 aminoacids. Soon after its cloning and mapping, a number of mutations andpolymorphisms related to PH1 have been sequenced. As of the beginningof the 21st century, the number of sequence variants reported in theHuman Gene Mutation Database (www.hgmd.cf.ac.uk) reaches over 50(34, 35, 57, 218).

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Polymorphic variantsTwo different haplotypes or polymorphic variants are recognized witha high frequency in European and North American populations: the‘major’ allele (frequency ~80%) and the ‘minor’ allele (frequency ~20%)(162). The frequency of the minor allele is ~3% in South Africans and~2% in the Japanese population (37, 46). The minor allele is characteri-zed by a 32C>T point mutation resulting in a substitution of the aminoacids proline11➔leucine (Pro11Leu). This minor allele is frequentlyassociated with a 74bp-duplication in the first intron, a 1020A>G pointmutation leading to an isoleucine340➔methionine (Ile340Met) substi-tution (159), and an Epstein-Barr-virus-like VNTR in the fourth intron(46). In the (South) African population, another polymorphic variantwith a c.976G>A point mutation, yielding a Val326Ile polymorphism isfound in ~12% (37).

Genetic basis of mitochondrial mistargeting of AGTThe minor allele alone does not cause PH1, but some interesting bio-chemical consequences have been observed in homozygous individu-als. The most intriguing is the so called mistargeting of a small pro-portion (5%) of the AGT enzyme to mitochondria instead of peroxisom-es (162). In other words, a proportion of AGT, which is normally locali-zed in the peroxisomal matrix, is imported into mitochondria. Themechanism behind this biochemical phenotype is considered to be achange in AGT protein folding. Normal AGT dimerizes after its synthe-sis. In this state, it can be imported in peroxisomes, but not in mito-chondria (106). In vitro studies have shown that the Pro11Leu poly-morphism creates a weak mitochondrial targeting sequence at the N-terminus of AGT (115, 158), which could create an alfa-helix at this siteof AGT. This in its turn prevents normal dimerization and 5% of AGT isimported in mitochondria in vivo (106, 137). Affinity for mitochondri-al import is increased by the additional occurrence of the c.508G>Amutation yielding a Gly170Arg substitution, which is the most commonmutation in PH1 found so far (106, 114, 115, 137, 158, 162).Mistargeting of AGT to liver mitochondria is then enhanced, resultingin about 90% of AGT routed to the mitochondria and only 10% toperoxisomes (162). The Pro11Leu polymorphism induces two otherchanges in the AGT enzyme: it decreases the catalytic activity by 70%and, at elevated temperatures, it decreases the efficiency of dimeriza-tion of AGT translated in vitro (114). Furthermore, it sensitizes AGT tothe deleterious effects of other mutations that probably would havebeen innocuous if they had occurred alone (137).

Co-segregation of the minor allele with other AGXT mutationsApart from the specific enzymic mistargeting phenotype, the minorallele also predisposes AGXT to the pathogenic effects of the three othercommonest sequence changes Ile244Thr, Phe152Ile, and Gly41Arg

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(114), resulting in aggregation of the AGT protein, as reviewed in theAPPENDIX 02. For example, the Ile244Thr mutation, which is the secondmost common mutation in patient groups studied so far, also segrega-tes with Pro11Leu. Its frequency is 9% in European and North Americanpopulations (201). AGT activity is low, and the phenomenon of mito-chondrial mistargeting is not seen in this genotype. Santana and asso-ciates demonstrated that Ile244Thr AGT forms aggregates in vitro (178).Proteolytic disposal in vivo could explain low AGT levels found in liverbiopsies of these patients. The Gly82Glu occurs on the background ofthe major allele and results in loss of AGT catalytic activity, possiblydue to failure of binding the co-factor (114, 160). For the Gly41Argmutation, segregation with the Pro11Leu polymorphism leads to aggre-gation into core-like structures in the peroxisomal matrix (49). WithoutPro11Leu (155), the specific AGT activity is only reduced in patients(114). Ser205Pro is only observed in Japanese PH1 patients on the majorallele. It renders AGT highly unstable and AGT is degraded subsequent-ly (144). A small insertion at codon 11 was found by an Italian group,c.33_34insC (155). A heterogenic picture was seen in these patients butno expression studies were carried out (3, 154). Apart from these speci-fic AGXT gene mutations, a large number of other AGXT mutations havebeen reported (2, 16, 34, 36, 37, 46, 49, 57, 113, 131, 135, 143, 160,165, 199, 200, 201, 218). An overview can be found at the website of theHuman Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac).

In summary, after the characterization of the AGXT gene and the firstPH1-related mutations in 1990 by Purdue et al. (161) a few cross-secti-onal studies had been reported on the prevalence of AGXT gene muta-tions (46, 77, 113, 199, 200, 201). Some genetic AGXT mutations hadbeen linked to specific defects of the AGT enzyme, such as intrape-roxisomal aggregation, loss of the pyridoxal phosphate binding siteand, most fascinatingly, a conformational change of the enzyme lea-ding to a predominantly mitochondrial instead of a solely peroxisomallocalized AGT enzyme (44, 105, 106, 158, 160, 162). However, theseinvestigations could not reveal the relationship between genetic cha-racteristics on the one hand and clinical characteristics and outcomeon the other hand.

PATHOPHYSIOLOGY OF RENAL DISEASE IN PRIMARY HYPEROXALURIAThe concentration process of urine in the kidneys results in increasingconcentrations of both oxalate and calcium. Since the solubility coeffi-cient of calcium and oxalate is low, they easily precipitate as calciumoxalate crystals. Urine is easily supersaturated with stone forming ions(166) but under normal conditions crystallization is prevented by thepresence of crystallization inhibitors such as citrate and magnesium.However, the high output of urinary oxalate in PH1 increases the pre-

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cipitation risk. This has already been investigated in animal models in1926 by Dunn and colleagues and in 1960 by Largiader, as reviewed byHockaday et al. (1964) (73). In the patient, these calcium oxalate cry-stals are considered to be the basis for stone formation. Although cry-stallization of oxalate with calcium was generally presumed to occur inthe renal parenchyma or medullary interstitium, the exact nature andextent of crystal deposition and its consequences for renal damage arenot known. Massive crystalluria in patients with a severe form ofhyperoxaluria could lead to early development of urolithiasis, nephro-calcinosis, and renal insufficiency due to insoluble and obstructiveproperties of calcium oxalate. Contrary to previous hypotheses, oxala-te itself is only toxic at extremely high concentrations (181) and is pre-dicted not to lead to changes in tubular epithelial functioning or dama-ge in vivo. However, the presence of crystalluria has been demonstra-ted in recurrent renal-stone formers, and appeared to be increasedafter oral sodium oxalate loading (167). In recent years, another mecha-nism has become the focus of stone research, namely binding of cry-stals to the tubular epithelium, which may be mediated by the expres-sion of the receptor CD44 and its ligands hyaluronan (HA) and osteop-ontin (OPN) (9, 101, 195-197). Asselman et al. have shown that theexpression of HA precedes crystal retention in experimental modelsand, together with OPN, it is also associated with nephrocalcinosis inkidneys of preterm infants and renal transplants (9, 195). Observationsin monolayer cell cultures show that HA expression can be inducedafter creation of an artificial wound in the monolayer. In these circum-stances, CD44, which is normally present basolaterally, is expressed atthe apical cell surface, as well as HA. They are visible until wound hea-ling is completed. In human renal epithelial cells, the expression ofCD44, HA and OPN could well follow damage due to passage of calciumoxalate crystals. Consequently, crystals may attach to these expressedmolecules, causing nephrocalcinosis. Hyaluronan has been shown tobind crystals in cell culture experiments of Verkoelen et al., in which itmay serve as a stone binding glue (197). The presence of these mole-cules for PH1 and their implications for clinical management are cur-rently unknown and warrant further investigation.

CLINICAL PRESENTATION AND CLINICAL STUDIES INPRIMARY HYPEROXALURIA TYPE 1After the description of some case reports in the second half of the pre-vious century, the first large patient cohort was described in Sweden,comprising 17 patients of Scandinavian origin (72). At that time, theenzyme deficiency had not yet been discovered and a complete dia-gnostic work up was therefore not possible for all patients. Upon thediscovery of AGT deficiency as the cause of PH1, many patients withsuspected PH1 were analyzed and published. In 2000, at the start of theproject leading to this thesis, a French cohort had been published

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(Cochat et al., 1995) (27), a Swiss cohort focused on the infantile pre-sentation (Leumann et al., 1987) (112) and an overview of 330 cases(Latta et al., 1990) (103). One phenomenon was recognized in all ofthese studies: PH1 is a very heterogeneous disease with respect to ageat presentation, outcome of renal function, and biochemical characte-ristics. The first symptoms in patients with primary hyperoxaluriawere usually related to renal stone disease, such as colic pain, hema-turia and/or recurrent urinary tract infection (103). However, nephro-calcinosis may also develop without any of these signs and symptoms.Some patients only become clinically symptomatic at the time end-stage renal disease has already developed. Systemic deposition of cal-cium oxalate may occur throughout the body when plasma oxalate con-centration rises above 20 μM and glomerular filtration rate falls below60ml/min/1.73m2 (136). The chemical composition of these systemicdepositions was also calcium oxalate (26, 70). The risk for systemicoxalosis increases sharply when the GFR comes down to 20ml/min/1.73m2 (136). When dialysis is started (GFR<10ml/min/1.73m2),further development of oxalosis cannot be prevented. Despite intensi-ve dialysis schedules, patients develop the most severe complicationsof primary hyperoxaluria due to systemic oxalate depositions, whichcan occur in many organs and tissues, like bones, muscle fibres andconnective tissues (18, 21, 194), and the nervous system, particularlythe interstitium of peripheral nerves (69). Other tissues are involved,such as the vascular system, the heart (21, 26, 194), myocardiac musclefibers (21, 194), tracheal cartilage (21), lungs (69), prostate (21), brains,meninges and in walls of congested meningeal vessels (70), choroidplexus, pineal gland, ovaries, fallopian tubes, uterus, thymus, salivaryglands, pancreas, bladder (52) and in joints (125). Consequences ofoxalosis range from frequent bone fractures and loss of visual acuity,to advanced neural damage, cardiac conductivity blocks, and arterialvessel obstruction with necrosis and gangrene, eventually leading toearly mortality (65, 69, 70, 119). Although the liver is the primary sitefor oxalate production, liver oxalate depositions have only been obser-ved infrequently (1, 69). The most striking features of systemic oxalo-sis are presented in APPENDIX 01.

The clinical pattern emerging from the initially published patientcohorts showed that infantile patients often presented with end-stagerenal disease, failure to thrive, metabolic acidosis, vomiting, anorexiaor anemia, generally preceding rapid progression of renal insufficien-cy. Although most patients presented within the first decade of lifewith renal involvement, presentation in adulthood was also frequentlyobserved. These observations resulted in a clinical classification of primary hyperoxaluria type 1 into three groups (29):1. a severe, neonatal or infantile form, with urolithiasis, nephrocal-

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Outcome, regarding preservation of kidney function or patientsurvival, was assumed to be poor in this group;

2. a mild form, with onset of symptoms in late adulthood, and afavourable prognosis of kidney function;

3. an intermediate group, comprising patients presenting in child-hood, with a slow decline of renal function over years and deve-lopment of ESRD in more that half of them.

Not all these observations were based on comprehensive epidemiolo-gical studies. Several case reports of patients with adult onset of symp-toms, who presented in end-stage renal disease (102) and reports ofpatients with neonatal PH1 with a relatively mild course argumentedagainst this classification (129, 203).

DIAGNOSTIC APPROACH TO PRIMARY HYPEROXALURIA TYPE 1Diagnosis of primary hyperoxaluria type 1 is based on clinical, meta-bolic, genetic and enzymatic studies. The gold standard of diagnosis isthe demonstration of absence, or decrease in peroxisomal AGT enzymeactivity. As human AGT is almost exclusively expressed in liver, thisrequires an invasive liver biopsy. Therefore, other less invasivemethods are currently regarded as the first choice in the diagnosticwork up. In this overview, the approach to diagnosis of primary hyper-oxaluria type 1 will be discussed. The appendix provides a table withreference values for relevant diagnostic tests.

Clinical diagnosisThe clinical presentation of PH1 is extremely heterogeneous. Patientsmay present with symptoms between 0 and at least 60 years of age.Symptoms vary from single urinary stones, recurrent urinary tractinfection and hematuria to all stigmata of end-stage renal disease. Inchildren, non-specific symptoms as failure to thrive, feeding problemsand vomiting may be the first findings. Weight gain and edema, loss ofappetite and fatigue may indicate renal insufficiency at any age. Sincecalcium oxalate is also deposited at other sites in the body apart fromthe kidneys, the longer the period of renal insufficiency exists, the morecalcium oxalate depositions can be found elsewhere in the body. Typicalbone lesions on X-ray and brown retinal maculae on fundoscopia (FIGURE

01.10) characterize systemic oxalosis in patients with severe renal fai-lure. Renal stones, nephrocalcinosis, and in the case of severe renal fai-lure a highly echo dense appearance of the kidney with loss of cortico-medullary differentiation are the most common abnormalities found byultrasound (FIGURE 01.7). Renal biopsy may reveal typical fan-shapedoxalate crystals (FIGURE 01.4) and signs of interstitial nephritis (27, 79,80, 103, 112, 130). In summary, symptoms of renal calcification, butalso signs of renal failure and of bone disease and visual impairmentmay be the first clues to initiate a diagnostic work up for PH1. In gene-

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ral, oxalate crystals can originate either from endogenous oxalate pro-duction in patients with primary hyperoxaluria, or excessive oxalateintake due to high dietary oxalate loads, or enhanced oxalate absorptionin patients with malabsorption syndromes or inflammatory bowel dis-orders, or decreased oxalate excretion in patients with end-stage renaldisease on dialysis. However, none of the clinical signs and symptomsis pathognomonic for a diagnosis of PH1. Therefore, any patient pre-senting with these clinical signs and symptoms should be furtherinvestigated for PH1

Metabolic studiesAssessment of patients for a diagnosis of primary hyperoxaluria canstart with metabolic analysis for elevated levels of oxalate in urine, plas-ma or peritoneal fluid.

UrineThe use of urinary metabolites in the diagnosis of PH1 is restricted topatients with a preserved renal function, since false negative resultsmay be obtained when renal function declines. In case of renal insuffi-ciency, one should proceed to analysis of plasma metabolites. Twomechanisms interfere with reliable determination of oxalate: crystalli-zation and ascorbate interference. For these confounders, urine is col-lected in acidified containers. If urine is kept at a pH<2, oxalateremains solved and does not crystallize with calcium ions. Meanwhile,the enzymatic conversion of ascorbate to oxalate in vitro is reduced,though it will take place during storage with time, even at low storagetemperatures (211). This may result in false positive values.

Assessment of urinary levels of oxalate and glycolate has always beenthe first line in the diagnostic assessment of PH1. Due to potential cir-cadian variation in urinary oxalate excretion (148), which parallels vari-ations in creatinine excretion, it is generally advised to study 24-hoursamples (128, 152). However, by calculation of the ratio of urinary oxa-late to creatinine [mmol/mol] and glycolate to creatinine in spontane-ously voided urine samples potential misinterpretation because ofsampling errors is avoided. Therefore, analysis of spot-urines producescomparable results to 24-hour urinary collections (88) making urinaly-sis in young children easier. For children, creatinine and oxalate excre-tion is higher at younger age. Therefore, age-related reference valueshave been obtained in a number of studies (15, 62, 111, 163, 198).Results of urinary oxalate excretion between adults and children mayalso be compared if expressed as mmol per 1.73m2 body surface areaper day (62, 128). For PH1, levels usually exceed 1 mmol per 1.73m2

body surface area. An elegant technique assessing urinary oxalate andglycolate from dried urine filter spots in a pediatric population wasdeveloped by Blau et al. (20).

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Values of urinary glycolate concentration in control subjects have beenreported in 13 studies, and range from 1 to 99.6 mg/24 hr, which isequal to 1 to 135 mmol/mol creatinine/24 hr (206). Urinary glycolateas assessed by gas chromatography produces valid and accurateresults (111). Using tetrahydrofuran, the extraction procedure for ana-lysis with gas chromatography was improved by Dietzen et al. (51). Therange of normal glycolate values reflects a considerable daily variabili-ty of urinary glycolate levels (206). Most reliable results are obtainedby expressing the results as the glycolate/creatinine ratio. Whether gly-colate levels in PH1 patients also vary to a great extent has not beeninvestigated. If so, it may contribute to the observation of normal uri-nary glycolate levels in 25% of PH1 patients, which is a major pitfall inthe diagnosis of PH1 based on urinalysis.

PlasmaIn patients with PH1, plasma levels of oxalate and glycolate not onlyrise in renal insufficiency, but may also be elevated in patients with apreserved renal function. Therefore, assessment of these metabolitesin plasma is of value for diagnosis in all patients with suspected PH1.However, in patients with preserved renal function, normal levels donot exclude PH1.

Elevated plasma oxalate concentration is a common observation inpatients with renal insufficiency not due to PH1. However, oxalatelevels in non-PH patients with renal insufficiency rarely exceed 50-60μmol/l (10 times upper range of reference values), in contrast to PH1patients in whom levels may rise to 200-300 μmol/l. Nevertheless, theisolated determination of plasma oxalate cannot always discriminatebetween primary hyperoxaluria or high levels of plasma oxalate due torenal insufficiency. Wolthers et al suggested that a plasma oxalate:cre-atinine ratio exceeding 0.1 and a calculated total quantity of oxalateremoved by dialysis exceeding 2 mmol to be supportive of a diagnosisof hyperoxaluria (214). Other causes of secondary hyperoxaluria, resul-ting in elevated plasma oxalate levels, may include intake of highamounts of vitamin C, and hyperoxaluria caused by inflammatorybowel disease or short bowel syndrome (31, 136, 150). The issue ofsecondary hyperoxaluria due to high amounts of vitamin C intakeremains controversial. Some clinical reports found a significant rise ofurinary oxalate excretion upon oral ascorbate loading (17, 71, 191).Two case reports found the occurrence of acute renal failure in other-wise healthy persons due to vitamin C supplementation of 2.5 g – 4 gper day (121, 139). The effect of ascorbic acid supplementation wasstudied in some controlled studies, using healthy volunteers and stoneformers (up to 10 grams per day) (25, 123, 182). Although the conver-sion rate of ascorbic acid into oxalate was 1-2%, it may become a clini-cally significant increase in patients with primary hyperoxaluria since

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the solubility of calcium oxalate in urine is very limited. However,others could not demonstrate this relationship (23, 192, 205, 211). Astudy assessing the fate of oral suppletion of isotopic ascorbic acid fee-dings found that ascorbic acid is only a minor contributor to oxalateexcretion in primary hyperoxaluria (10). No other studies assessed thein vivo ascorbate conversion in patients with biochemically or geneti-cally determined PH1.

Determination of glycolate concentration in plasma in addition to plas-ma oxalate has been suggested to allow discrimination of PH1 patientsfrom patients with other causes of renal insufficiency (87, 117, 118).However, since little studies in patients with PH1 having end-stage renaldisease have been performed, the sensitivity of plasma glycolate testingis not known. On the other hand, the specificity seems to be high sincestudies in patients who have received a curative liver transplantationshow a decline of glycolate up to normal values within days (87).

Collection procedure and preparationAs vitamine C in plasma and other potential sources of glyoxylate maycause in vitro oxalate synthesis after collection of a blood sample,resulting in false positively elevated levels of plasma oxalate, plasmashould be deproteinized quickly after it has been drawn in pre-cooledheparine vacutainers and stored at - 20 ºC and storage time should beas short as possible (149, 151, 213). Interference of ascorbate with themeasurement of plasma oxalate is prevented by acidification, prior toanalysis, since alkaline pH could lead to generation of oxalate fromascorbate (141, 151).

Analytical methodsPlasma oxalate analysis by means of in vivo dilution, a radiochemicaltechnique using labeled [14C]oxalate, has by far provided the mostaccurate measurement of plasma oxalate concentration. The referencevalue has been determined by this method as 1.39 (range 1.04 to 1.78)(31, 74, 157). As this assay is impracticable as it uses a radioactivelabel, other assays have been developed. Enzymatic measurementsusing oxalate oxidase reactions are most prone to false results byascorbate interconversion (40, 96, 107). For ion chromatography(HPLC), the main problem is in-column conversion of endogenousascorbate to oxalate, which can be avoided either by ascorbate oxida-tion with iron(III)ions (97) or by means of boric acid dilution (216). Gaschromatography-mass spectrometry (GC-MS) is probably the mostaccurate technique though more laborious than ion chromatography.Its reliability is very high because of the use of stable isotope labeledinternal standards (87). Plasma oxalate levels in healthy persons have been measured withthese different techniques. Levels range from 0.4-6.0 μM, depending on

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the method of analysis (152). For PH1 patients with preserved renalfunction, plasma oxalate levels may be within the normal range. Levelsgradually exceed 10 μM when renal function declines from 80 to 40ml/min/1.73m2, however, plasma oxalate levels rise progressivelyabove 30 μM when the glomerular filtration rate falls below 40ml/min/1.73m2 (136).

Plasma glycolate measurements by HPLC and GC-MS methods haverevealed glycolate levels of 7.5 ± 2.4 μM in healthy persons (87).Another sensitive HPLC procedure was developed by Hagen et al. (67).Plasma glycolate levels of PH1 patients with preserved renal functioncan exceed 20 times the upper limit of the normal reference range andare therefore highly discriminative in the diagnosis of PH1 (118). InPH1 patients on hemodialysis or peritoneal dialysis, plasma glycolatelevels may even rise up to 150 times the normal range (117), whereasglycolate remains normal in primary hyperoxaluria-unrelated end-stage renal disease.

Peritoneal fluidOxalateThe use of dialysate in the diagnosis of PH1 in patients on peritonealdialysis (PD) has been investigated in one case-control study: four PH1patients on PD and four controls. This study revealed an oxalate/ cre-atinine ratio of 512 (range 265-638) mg/g in four PH1 patients on PD ascompared to 130 (range 64-191) mg/g in PD patients with other under-lying diseases (124).

GycolateOne study has been published on glycolate levels in the dialysate of aPH1 patient in comparison with five non-PH PD patients, which showedsignificantly elevated levels of glycolate in the PH patient: 48.3μmol/day in the PH1 patient versus 19.6 (range 15.1-27.5) μmol/day inthe non-PH PD patients (215). The analysis was performed by means ofstandard organic acid analysis using gas chromatography without anisotopic internal standard as control.

Though analysis of oxalate and glycolate in dialysate fluid is not wide-ly practiced, it seems of additional diagnostic value.

Genetic diagnosisAfter characterization of the AGXT gene as described above, expressionstudies showed the pathogenicity of the most common mutations,including the amino acid substitutions Gly170Arg, Gly82Glu andGly41Arg (114).

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Enzymatic diagnosisFor patients in whom the diagnosis remains uncertain after urinary andgenetic analyses, assessment of the AGT enzyme activity in a liver bio-psy specimen may be the ultimate diagnostic procedure. The analysis ofthe AGT enzyme was first performed in 1972 (138, 172). The analysis waslater performed using a Cobas Fara centrifugal analyzer (83, 84), or ana-logous procedures and can be performed in a semi-automated way (175). The AGT enzyme has a considerable range in residual in vitro activity fordifferent genotypes in PH1. Three main forms of AGT deficiency arerecognized (48):

1. absence of both immunoreactive and catalytically active AGT(CRM-/ENZ-); the AGT activity may be below the detection level;

2. presence of immunoreactive AGT but absence of catalytically acti-ve AGT (CRM+/ENZ-);

3. presence of both immunoreactive and catalytically active AGT(CRM+ /ENZ+): the residual in vitro activity ranges from 15% up to50% of normal activity. The inconsistency of the apparent in vitroactivity and lack of in vivo activity of the enzyme in the latter situ-ation is due to mitochondrial mistargeting of AGT. In all these 3situations, the diagnosis of PH1 is confirmed, though heterozygo-te carriers may also be detected with 50% residual enzyme activi-ty. However, no reports have demonstrated hyperoxaluria in car-riers. Therefore, it is probably without clinical significance. Incase of doubt when high residual activity of AGT is found, AGTmistargeting to mitochondria can be assessed by immunocyto-chemical localization studies of the enzyme (33), though the mito-chondrial mistargeting phenotype should have been traced bygenetic sequencing at this stage, revealing the Gly170Arg – or pos-sibly Phe152Ile – genotype (158).

Prenatal diagnosisMolecular genetics is the method of choice for prenatal diagnosis, usingmutation analysis (173). It can be used in the first trimester of pregnancy.

THERAPEUTIC APPROACH TO PRIMARY HYPEROXALURIA TYPE 1Treatment of patients with PH1 is mainly centered on influencing themetabolism of oxalate and glyoxylate, prevention of renal sequelae,treatment of urolithiasis and, in case of end-stage renal disease, insti-tution of renal replacement therapy.

Conservative treatmentAs with renal stone disease in general, conservative management con-sists of increasing fluid intake to dilute urine if renal function permits,dietary modifications, and the administration of pharmacologic agentsthat minimize the risk of supersaturation by increasing the urinary

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concentration of inhibitory substances (81). Maintaining a good hydrationis especially important in patients at risk for dehydration, for example incase of diarrhoea. In children, who are at risk for rapid dehydration, earlyinstitution of naso-gastric tube hydration or intravenous fluid admi-nistration is mandatory. Continuous naso-gastric tube hydration duringnighttime should be considered in small children or patients with alreadysevere nephrocalcinosis and renal damage. For dietary measures, a suffi-cient calcium intake is advised in order to bind any dietary oxalate in thedigestive tract before it can be absorbed and excreted by the kidneys.Although excessive ingestion of dietary oxalate should be avoided, abso-lute elimination of oxalate containing food is probably less importantsince the ingested amount of oxalate is relatively small compared to endo-genously produced oxalate. Citrate, 0.15 g/kg, is considered to be apotent chelator of calcium in urine but under normal conditions it is notsufficient to chelate more than a fraction of the calcium present (85).However, its use in humans strongly inhibits calcium oxalate nucleationand aggregation (89, 110, 179, 186). Potassium citrate is preferred to sodi-um citrate since it prevents high sodium intake and secondary hypercal-ciuria due to high sodium intake. In addition, citrate acts as an alkalini-zing agent, further reducing the risk of crystallization (168, 220).

Magnesium salts are sometimes used as modifiers of nucleating agentsbut magnesium may only be added to potassium citrate therapy to fur-ther inhibit calcium oxalate crystallization (122, 220). An adverseaffect of magnesium administration is the potential occurrence ofdiarrhoea which may lead to dehydration, greatly enhancing the riskfor crystallization of calcium oxalate in the kidney.

The best evidence for successful pharmacological intervention inpatients with PH1 comes from studies assessing the use of pyridoxineand orthophosphate. Animal studies had already studied the effects ofpyridoxine on oxalate metabolism (60). Pyridoxine was first describedfor treatment of patients with PH1 in 1967 (185) but the effects wereconflicting (63). Orthophosphate alone was known for its inhibitoryeffect on crystal formation, though the exact mechanism of this phe-nomenon was not clear (85). A long-term follow-up study in PH1patients evaluated the use of pyridoxine and orthophosphate andfound a decreased urinary calcium oxalate crystallization and preser-vation of renal function (129). An intake of more than 1000mg per daymay lead to reversible, peripheral neuropathy (190). For pyridoxine, aninitial dose of 5 mg/kg is usually prescribed. The potential decline ofurinary oxalate should be awaited for 2-3 months after which the dosa-ge is optimized under control of urinary oxalate excretion. Usually,either citrate or orthophosphate is added to the treatment regimen. Fororthophosphate no further studies are available as to assess its effec-tiveness.

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Transplantation:

Kidney transplantation, Liver transplantation or Combined liver-kidney transplantation

Currently, a definitive cure of the metabolic enzyme deficiency in PH1is only feasible through liver transplantation. This was initially perfor-med at the time end-stage renal disease had ensued under carefullyoptimized conditions (104), but later on, pre-emptive liver transplan-tations were introduced to prevent development of end-stage renaldisease. Combined liver-kidney transplantations were also performedto correct both the enzymatic defect and the renal insufficiency.

For patients with PH1, four transplantation procedures are known: (1) sole kidney transplantation; (2) pre-emptive liver transplantation,(3) combined liver-kidney transplantation, or (4) sequential liver-kid-ney transplantation, in which the kidney transplantation is plannedafter reduction of plasma oxalate levels, in order to reduce oxalate bur-den for the kidney transplant. For each of these options, systematic cli-nical evidence is collected in different cohorts, and adverse effects areconsiderable: option (1) was thought to be prone for early graft failuredue to recurrence of oxalate depositions; option (2) would be reservedto patients who do not respond to conservative treatment, but nopatient characteristics could determine this; option (3) needed carefulorgan selection and operative care; and for option (4), immunizationproblems were expected since organs from different donors were goingto be transplanted. A European cohort study that collected data byquestionnaires, found that the outcome of kidney function was inver-sely related to the time between onset of dialysis treatment and trans-plantation. They found excellent results with combined liver-kidneytransplantations (28, 93, 94) which was confirmed by a single centerexperience (133). However, incompleteness of data might have resultedin bias towards positive outcome. In a United States follow-up survey,renal allograft survival was equal in patients who had undergone a soli-tary kidney, as compared to those who had received a combined liver-kidney transplantation; at the same time, the patient survival was betterfor kidney transplanted recipients (176). A high morbidity and mortali-ty rate was observed in infants and young children undergoing comb-ined liver-kidney transplantation which suggested a pre-emptive livertransplantation or a combined liver-kidney transplantation before rea-ching end-stage renal disease (54). Few reports have reported the suc-cessful use of pre-emptive liver transplantation in order to prevent dia-lysis-induced oxalosis (146). A better prediction of outcome of patientswas needed for appropriate choice of transplantation.

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ZELLWEGER SPECTRUM DISORDERSThe Zellweger spectrum disorders (ZSDs) belong to the group of peroxi-some biogenesis disorders (PBDs), that are characterized by a defect inperoxisomal assembly (202). The failure to assemble peroxisomes inthe cells of these patients, results in a failure to import peroxisomalenzymes into the peroxisomal matrix. Subsequently, most of theseenzymes, after their synthesis in the cytosol, are rapidly degraded, andmultiple peroxisomal functions are lost. However, the AGT enzyme wasreported to be stable in the cytosol just like a few other peroxisomalenzymes including catalase (204). We studied the clinical picture ofpatients with ZSDs, to observe potential effects of cytosolic localizedAGT on glyoxylate metabolism. The prototype of PBDs are Zellwegersyndrome patients, with an early lethal course, but other patients havemilder phenotypes. Still, many have a severe physical and mental retar-dation, although to different extents, and mild cases survive into adult-hood, and are socially and intellectually educable (156). Clinical featu-res include neurodevelopmental impairment, retinopathy, perceptivedeafness, and hepatic dysfunction (202). Renal involvement with uroli-thiasis, nephrocalcinosis and hyperoxaluria was observed in threepatients, despite normal AGT activity. The incidence of hyperoxaluriain ZSD patients and its clinical implications was, however, unknown.

SECONDARY HYPEROXALURIAAs previously stated, dietary absorption of oxalate is estimated toaccount for approximately 10-50% of the total daily oxalate excretion(76, 209). Secondary hyperoxaluria has four pathophysiological ori-gins: 1. an increased ingestion of oxalate from dietary sources such asrhubarb, spinach, cocoa, tea, parsley, pepper, peanuts, beets; 2. anincreased absorption due to bowel disorders (187) such as cystic fibro-sis (64, 78, 82, 183), inflammatory bowel disease, ileal resection; 3. adecreased clearance of oxalate due to renal insufficiency (214); or 4. asa consequence of long term parenteral nutrition in preterm infants(22). Even without specific disorders of the gastrointestinal tract, theremay be a higher oxalate uptake from the diet by recurrent renal-stoneformers (167). All these mechanisms can lead to elevated levels of uri-nary oxalate which may become as high as in primary hyperoxaluria,although levels are generally lower (82, 184). Plasma oxalate may alsobe increased (64, 78, 82, 183, 187). Contrary to what is observed in pri-mary hyperoxaluria, levels of glycolate and L-glycerate are normal inthese patients. Secondary hyperoxaluria may lead to severe morbiditywith urolithiasis or nephrocalcinosis as observed especially in patientswith malabsorptive syndromes, and eventually renal insufficiency(150, 184) or even ESRD (19). However, large cohorts have never beendescribed. In dialysis-related secondary hyperoxaluria, extra renaldepositions of calcium oxalate are rare and do not follow the relentlesspattern of PH1 (119).

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The mechanism leading to hyperoxaluria in these disorders is not alwa-ys clear. However, for malabsorptive diseases, several hypotheses existby which hyperoxaluria is generated. Three mechanisms are mainlysuggested to give rise to absorptive hyperoxaluria: first, calcium bindsto fatty acids, in steatorrhoea, which is present in patients with malab-sorption. Because of this, less calcium is available to bind oxalate andmore oxalate is available for uptake in the colon. A higher fat intake perse, however, does not necessarily contribute to higher excretion of uri-nary oxalate (13, 120). Secondly, as a consequence of elevated fattyacid concentration in the colon, the permeability of the colon for oxa-late absorption increases, resulting in more oxalate uptake. Thirdly, adepletion of the oxalate degrading bacteria is seen in some patientswith cystic fibrosis, possibly due to frequent use of antibiotics. Thisalso leads to higher oxalate concentrations in the gut, with elevatedoxalate uptake (183). Dietary restrictions of oxalate containing pro-ducts can sometimes prevent or decrease the severity of secondaryhyperoxaluria. However, it can be a persistent clinical problem inmalabsorptive diseases. For patients on dialysis, hyperoxaluria andhyperoxalemia are caused by the inability of dialysis techniques toremove oxalate sufficiently, and oxalate accumulation occurs. Plasmalevels can rise up to 116 μmol/l and systemic oxalosis with organinvolvement has been reported frequently (19, 55, 127, 147, 189).

AIM OF THE STUDYResearch has elucidated parts of the complicated genetic and metabo-lic changes that constitute the basis of primary hyperoxaluria type 1.However, a number of questions remain to be answered.

One of the most difficult issues in primary hyperoxaluria type 1 (PH1)is the heterogeneity of the disease, at the genetic, biochemical and cli-nical level. This heterogeneity prevents a clear prediction of diseaseseverity or of outcome of patients based on patient characteristics. Themain aim of this study is to unravel this heterogeneity. For this, a nati-onwide cohort will be recruited, and patient characteristics will be des-cribed, at the genetic, biochemical and clinical level. This facilitates thecalculation of the prevalence of PH1 in The Netherlands, and may leadto a correlation between genetic and biochemical studies on the onehand, and clinical outcome of patients on the other hand. Differentoptions for treatment will also be assessed in the patient cohort, inclu-ding conservative treatment with pyridoxine, and transplantations.Concerning the issue of transplantation, either a (1) kidney, (2) pre-emptive liver, (3) combined liver-kidney, or (4) sequential liver-kidneytransplantation is available. For each of these options, systematic cli-nical evidence is lacking and adverse effects are considerable. At thetime of onset of this study, data on the outcomes of the different trans-plantation policies were too conflicting to draw definite conclusions

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for therapeutic strategies. To address this issue, we decided to analyzeall transplanted patients in our cohort and we designed a strategy fortype and timing of transplantations, based on the clinical, biochemicaland genetic experience in our national cohort.

Diagnostic studies include the use of mutation analysis of the AGXTgene. The applicability of DNA diagnosis for patients with primaryhyperoxaluria was not known in The Netherlands. Furthermore, therelationship between AGXT gene mutations and the clinical phenotypeof patients with PH1 was unclear. We aim to assess the spectrum ofAGXT gene mutations in Dutch patients with PH1 and evaluate the useof DNA diagnosis in PH1, as a rapid, non-invasive tool in diagnosticscreening. Using the clinical information of the Dutch patient cohort,we will try to relate the clinical phenotype to AXGT gene mutations.

Another issue concerning screening for PH1 is the collection of urinefor oxalate and glycolate measurements. This is usually performed inacidified containers, which exposes patients to the hazards of hydro-chloric acid. No systematic studies have addressed its use in PH1 andwe investigate whether hydrochloric acid should still be applied, or itcould be added to the urine collection after arrival of the urine speci-men at the laboratory.

Regarding the occurrence of hyperoxaluria and renal involvement insome patients with Zellweger spectrum disorders, our aim is to studya cohort of these patients to assess the incidence of hyperoxaluria inthem, and the potential implications for renal involvement.Biochemically, patients with Zellweger spectrum disorders lackperoxisomes and therefore, the in vivo results of cytosolically localizedAGT enzyme becomes apparent. The correlation between the clinicalseverity of this neurological disease and the incidence of renal invol-vement and hyperoxaluria will be studied.

Finally, we initiate research to evaluate potential new treatment in PH1and to investigate a biochemical model that facilitates studies of thebiochemical origin of oxalate. For patients with a preserved renal func-tion, urinary excretion of oxalate is regarded to reflect endogenousoxalate production, unless renal insufficiency occurs. New treatmentcould be targeted to try to reduce endogenous oxalate synthesis.Evaluation of its efficacy is only possible if a careful estimation ofendogenous oxalate synthesis is available. Since endogenous oxalate isproduced by the liver, the rate of appearance of oxalate in plasmawould accommodate this need. We use an in vivo isotope dilutionmethod to calculate the rate of appearance of oxalate in plasma inpatients and control subjects. CHAPTER 01

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The Agxt -/- mouse, an animal model for primary hyperoxaluria type 1,was recently developed by Salido et al. (177). The Agxt -/- mouse is defi-cient for the AGT enzyme, and displays high levels of urinary oxalate.Development of rational therapies that interfere with endogenous oxa-late synthesis is hampered by the lack of knowledge on the exact sour-ces of oxalate, apart from its direct precursor glyoxylate. Therefore, wewill isolate hepatocytes from the Agxt -/- mouse to study the contribu-tion of potential precursors of oxalate synthesis.

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