43 Primary Hyperoxalurias

Pierre Cochat, Marie-Odile Rolland

43.1 Primary Type 1 – 541 43.1.1 Clinical Presentation – 541 43.1.2 Metabolic Derangement – 542 43.1.3 Genetics – 542 43.1.4 Diagnosis – 542 43.1.5 Treatment and Prognosis – 542

43.2 Type 2 – 545 43.2.1 Clinical Presentation – 545 43.2.2 Metabolic Derangement – 545 43.2.3 Genetics – 545 43.2.4 Diagnosis – 545 43.2.5 Treatment and Prognosis – 545

43.3 Non-Type 1 Non-Type 2 Primary Hyperoxaluria – 545

References – 545 540 Chapter 43 · Primary Hyperoxalurias

Oxalate Metabolism is a poorly soluble end-product of the metabo- verted into oxalate by lactic acid dehydrogenase (LDH); lism of a number of amino acids, particularly glycine, it can also be converted into glycolate by glyoxylate and of other compounds such as sugars and ascorbic reductase (GR) and into glycine by glutamate: glyo- acid. The immediate precursors of oxalate are glyo- xylate aminotransferase (GGT). Glycolate can also xylate and glycolate (. Fig. 43.1). The main site of syn- be formed from hydroxypyruvate, a catabolite of glu- thesis of glyoxylate and oxalate is the liver , cose and . Hydroxypyruvate can be con- which can also detoxify glyoxylate by reconversion into verted into L-glycerate by LDH and into D-glycerate glycine, catalyzed by alanine: glyoxylate aminotrans- by hydroxypyruvate reductase (HPR), which also has ferase (AGT). In the cytosol, glyoxylate can be con- a GR activity.

X

. Fig. 43.1. Major reactions involved in oxalate, glyoxylate and HPR, hydroxypyruvate reductase; LDH, lactate dehydrogenase; glycolate metabolism in the human hepatocyte. AGT, Alanine: X, metabolic block in primary hyperoxaluria type 1 (PH1), O, meta- glyoxylate aminotransferase; GGT, glutamate: glyoxylate amino- bolic block in primary hyperoxaluria type 2 (PH2) transferase; GO, glycolate oxidase; GR, ;

. Fig. 43.2. Bone histology in primary hyperoxaluria type 1: calcium oxalate deposition shown by polarized light microscopy 541 43 43.1 · Primary Hyperoxaluria Type 1

Renal Involvement Primary hyperoxalurias (PH) are rare diseases which are PH1 presents with symptoms referable to the urinary tract characterized by overproduction and accumulation of in more than 90% of the cases: loin pain, , urinary oxalate in tissues. tract infection, passage of stones, , uremia, PH1 caused by deficiency or mistargeting of alanine: metabolic acidosis, growth delay, and . Oxalate ex- glyoxylate aminotransferase (AGT) in liver erts a toxic effect on mitochondrial function of renal epithe- is the most frequent and most severe form. Deposits lial cells and therefore leads to direct tubular damage [2]. of calcium oxalate crystals in the kidney lead to stones, However, the most common presentation is stone disease. nephrocalcinosis and deteriorating kidney function, Calculi – multiple, bilateral and radio-opaque - are made of while bone disease is the most severe extrarenal in- calcium oxalate. Nephrocalcinosis, best demonstrated by volvement. Careful conservative treatment (high fluid ultrasound, is present on plain abdomen x-ray at an ad- intake, calcium-oxalate crystallization inhibitors, and vanced stage. pyridoxine) should be started early as it may prolong The median age at initial symptoms is 5 to 6 years, kidney survival. Liver and are ranging from birth to the 6th decade. End-stage renal dis- the final current options. Hyperoxaluria and hyper- ease (ESRD) is reached by the age of 25 years in half of glycoluria are indicative of PH1. patients [1]. PH2, caused by glyoxylate-reductase (GR) deficien- The infantile form often presents as a life-threatening cy in the liver and other tissues, is less frequent and less condition because of rapid progression to ESRD due to severe, and treatment less demanding. Hyperoxaluria both early oxalate load and immature glomerular filtration without hyperglycoluria and increased urinary excre- rate (GFR): one-half of the patients experience ESRD at tion of L-glycerate differentiate it from PH1. the time of diagnosis and 80 % develop ESRD by the age of In addition, there are isolated reports of PH with- 3 years [3, 4]. out either AGT or GR deficiency, so that it is likely that there is at least another form of PH (PH3) yet to be Extrarenal Involvement explained. When GFR falls to below 30 to 50 ml/min per 1.73 m2, continued overproduction of oxalate by the liver along with reduced oxalate excretion by the kidneys leads to a critical Primary hyperoxaluria (PH) results from endogenous saturation point for plasma oxalate (Pox >30 to 50 µmol/l) overproduction of oxalic acid and accumulation of oxalate so that oxalate deposition occurs in many organs [5]. within the body. The main target organ is the kidney since Bone is the major compartment of the insoluble oxalate oxalate is excreted in the leading to nephrocalcinosis, pool and the bone oxalate content is higher (15 to 910 µmol recurrent urolithiasis and subsequent renal impairment. oxalate/g bony tissue) than among ESRD patients without Primary hyperoxaluria is associated with increased urinary PH1 (2 to 9 µmol/g). Calcium oxalate crystals accumulate excretion of glycolate in PH1, and of L-glycerate in PH2 first in the metaphyseal area and form dense suprametaphy- (. Fig. 43.1). Secondary hyperoxaluria also occurs and is seal bands on x-ray. Later on, oxalate osteopathy (. Fig. attributed to increased intestinal absorption or excessive 43.2) leads to pain, erythropoietin-resistant anemia, and intake of oxalate. spontaneous fractures. Along with the skeleton, systemic involvement includes many organs because of progressive vascular lesions: heart 43.1 Primary Hyperoxaluria Type 1 (cardiomyopathy, arrhythmias, and heart block), nerves (polyradiculoneuropathy), joints (synovitis, chondrocalci- 43.1.1 Clinical Presentation nosis), skin (calcium oxalate nodules, livedo reticularis), soft tissues (peripheral gangrene), retina (flecked retinopa- PH1, is the most common form of PH. Five different pres- thy) and other visceral lesions (e.g. intestinal infarction, entations are described: i) a rare infantile form with early hypothyroidism) [1]. nephrocalcinosis and ; ii) a late-onset form Systemic involvement – named oxalosis – is responsible with occasional stone passage in late adulthood; iii) the for poor quality of life leading to both disability and severe most common form with recurrent urolithiasis and pro- complications. Indeed PH1 is one of the most life-threaten- gressive renal failure leading to a diagnosis of PH1 in child- ing hereditary renal diseases, mainly in developing coun- hood or adolescence; iv) a rare condition where the diagno- tries where the mortality rate may reach 100% in the absence sis is first made following recurrence in a transplanted kid- of adequate treatment [1]. ney; and v) pre-symptomatic subjects in whom PH1 is discovered from family history [1]. 542 Chapter 43 · Primary Hyperoxalurias

43.1.2 Metabolic Derangement polymorphism which plays an important role in pheno- type determination [13]. DNA analysis among different PH1 is due to a deficiency or to a mistargeting to the mito- ethnic groups has revealed the presence of specific muta- chondria of the liver-specific pyridoxal-phosphate-depen- tions, founder effects and phenotype-genotype correla- dent peroxisomal enzyme AGT [6]. The resulting decreased tions among North-African, Japanese, Turkish and Paki- transamination of glyoxylate into glycine leads to subse- stani populations [18]. quent increase in its oxidation to oxalate, a poorly soluble end-product. In patients with a presumptive diagnosis of PH, 10 to 30% are identified as non-PH1 because AGT ac- 43.1.4 Diagnosis tivity and immunoreactivity are normal [7]. Among PH1 patients, 75% have undetectable enzyme activity (enz-) and The diagnosis of PH1 is still being often delayed for years the majority of these also have no immunoreactive protein following initial symptoms. The combination of both clini- (cross reacting material, crm-). In the rare enz-/crm+ pa- cal and radiological signs is a strong argument for PH1, i.e. tients, a catalytically inactive but immunoreactive AGT is the association of renal calculi, nephrocalcinosis and renal found within the peroxisomes. The remaining PH1 patients impairment; family history may bring additional informa- have AGT activity in the range of 5 to 50% of the mean tion. and infrared spectroscopy are of major normal activity (enz+), and the level of immunoreactive interest for identification and quantitative analysis of crys- protein parallels the level of enzyme activity (crm+). In tals and stones, showing calcium oxalate monohydrate crys- enz+/crm+ patients, the disease is caused by a mistargeting tals (type Ic whewellite) with a crystal number >200/mm3 of AGT: about 90% of the immunoreactive AGT is localized in case of heavy hyperoxaluria [19]. Such crystals can in the mitochondria instead of in the peroxisomes, where also be identified in urine or tissues by polarized light mi- only 10% of the activity is found; almost all patients who are croscopy or infrared spectroscopy. Fundoscopy may show pyridoxine-responsive are in this group [8]. Interestingly, flecked retina. human hepatocyte AGT, which is normally exclusively lo- In patients with normal or significant residual GFR, calized within the peroxisomes, is unable to function when concomitant hyperoxaluria and hyperglycoluria are indica- diverted to the mitochondria. However patients with a tive of PH1, but some patients do not present with hyperg- X primary – e.g. Zellweger syndrome lycoluria. In dialysed patients, plasma oxalate (± glycolate): – do not exhibit hyperoxaluria. ratio and oxalate (± glycolate) measurement in dialysate may be contributive [20]. A definitive diagnosis of PH1 requires the measurement 43.1.3 Genetics of AGT activity in a liver biopsy. Despite controversial in- formation about the relationship between AGT activity and PH1 is the most common form of PH (1:60,000 to 1:120,000 the severity of the disease [11], liver biopsy assessment is live births per year in Europe) [1, 9]. Due to autosomal re- mandatory if a is being considered. cessive inheritance, it is much more frequent when parental Mutation analysis is based on the sequencing of the 11 consanguinity is present. Indeed it is responsible for less exons from the index case and gene segregation is checked than 0.5% of ESRD in children in Europe versus 10.4% in in both parents. In the presence of a typical presentation, Kuwait [10]. mutation analysis of the most frequent mutations according The AGT gene (AGXT) is a single copy gene located at to local background may provide a useful first line test with- the telomeric end of chromosome 2q36-q37; the 43 kDa pro- out liver biopsy [16]. tein contains 392 amino acids. Polymorphisms have been Prenatal diagnosis can be performed from DNA ob- identified: the most common in Europe and North America tained from crude chorionic villi or amniocytes, on the ba- is P11L, which introduces a weak mitochondrial mistarget- sis of a restricted analysis of exons including the familial ing sequence at the N-terminal end of the protein. mutation. Such a procedure allows the identification of More than 50 mutations, some of them more frequent, normal, affected and carrier fetuses. have been identified so far. They affect either the enzyme or its targeting: G82Q is associated with loss of AGT activity; I244T with increased AGT degradation; G41R with in- 43.1.5 Treatment and Prognosis traperoxisomal AGT aggregation; G170R with peroxisome- to- mistargeting, sometimes with significant Supportive Treatment AGT catalytic activity; G170R and F152I with pyridoxine Conservative measures should be started as soon as the responsiveness; homozygous patients for the 33insC muta- diagnosis has been made and even suspected. The aims are tion with ESRD during infancy [11-17]. I244T and G170R to decrease oxalate production and to increase the urinary mutations are common in European and North-American solubility of calcium oxalate. The risk of stone formation is patients (~40% of mutant alleles) and interact with the P11L increased when urine oxalate exceeds 0.4–0.6 mmol/l, 543 43 43.1 · Primary Hyperoxaluria Type 1

especially if urine calcium exceeds 4 mmol/l; therefore amounts of oxalate [8]. In such patients, Pox ranges between supportive therapy should be adapted to keep concentra- 70 and 150 µmol/l (control values <7.4 µmol/l) (. Table tions of oxalate and calcium below these limits. This should 43.1). Therefore daily hemodialysis (6-8 h per session) using be attempted by giving high fluid intake (>2 l/m2 per day) high-flux membranes would be required but such a strategy and supported by calcium-oxalate crystallization inhibi- cannot be routinely used [6]. The challenge is to keep pre- tors, such as citrate (potassium or sodium), 100 to 150 mg/ dialysis Pox below 50 µmol/l in order to limit the progres- kg per day in 3 to 4 divided doses [9, 21]. When it is not sion of systemic oxalosis. Conventional long-term hemodi- available, crystallization inhibition may be obtained by alysis is generally contraindicated because it only prolongs using sodium bicarbonate, magnesium or orthophosphate a miserable existence. [9]. Diuretics require careful management: furosemide will The benefit of (pre-) post-transplantation hemodialysis maintain a high urine output with the risk of an increased is still debated and should be limited to patients with either calciuria whereas the diuretic effect of hydrochlorothiazide oliguria or severe systemic burden and subsequent long is less marked but is associated with an appreciable de- lasting oxalate release from skeleton. crease of calcium excretion. Restriction of dietary oxalate intake (beet, root, strawberries, rhubarb, spinach, coffee, Kidney transplantation allows significant removal of solu- tea, nuts) has limited influence on the disease as oxalate ble Pox. However, because the biochemical defect is in the of dietary origin contributes very little to hyperoxaluria in liver, overproduction of oxalate and subsequent deposition PH [9]. Calcium restriction is not recommended, because in tissues continues unabated. The high rate of urinary oxa- less calcium would then bind oxalate and form insoluble late excretion originates from both ongoing oxalate produc- calcium-oxalate complexes in the gut. Ascorbic acid sup- tion from the native liver and oxalate deposits in tissues. plementation is not recommended as it is a precursor of Due to oxalate accumulation in the graft, isolated kidney oxalate. transplantation is no longer recommended, because of a The absence of intestinal oxalate-degrading bacterium 100% recurrence rate leading to poor graft survival and pa- Oxalobacter formigenes has been found to be associated with tient quality of life [23]. Indeed, renal transplantation does hyperoxaluria, so that increased amounts of such a micro- not prevent the progression of skeletal and vascular compli- organism in the gut might decrease disposable oxalate. cations. The chances of a successful transplantation are un- The main purpose of therapy is to lower both Pox and related to residual AGT activity but success is improved if it plasma calcium-oxalate saturation. The effects of conserva- is performed preemptively. Good results have been report- tive measures can be assessed by serial determinations of ed in selected patients after early renal transplantation with crystalluria score and calcium oxalate supersaturation soft- ware [21, 22]. Pyridoxine (cofactor of AGT) sensitivity (i.e. >30% re- . Table 43.1. Plasma and urine concentrations of oxalate, duction of urinary oxalate excretion) is found in 10–30% of glycolate and L-glycerate: control values [8, 9] patients, so that it must be tested early at a daily dose of 2–5 mg/kg with stepwise increase up to 10–20 mg/kg as mega- Urine Oxalate per <0.50 mmol/1.73 m2 day doses of pyridoxine may induce sensory neuropathy [9]. Response to pyridoxine, best detected by oxalate and gly- Oxalate: age <1 year <0.20 mmol/mmol colate measurement, may delay the progression to ESRD creatinine 1–4 years <0.13 mmol/mmol 5–12 years <0.08 mmol/mmol [3, 21]; the patients most likely to respond are those with adult <0.07 mmol/mmol homozygous G170R or F152I mutation, who also experi- 2 ence preserved renal function over time under adequate Glycolate child <0.55 mmol/1.73 m per day adult <0.26 mmol/1.73 m2 treatment [17]. The treatment of stones should avoid open and percu- Glycolate: age <1 year <0.07 mmol/mmol taneous surgery because further renal lesions will alter GFR. creatinine 1–4 years <0.09 mmol/mmol 5–12 years <0.05 mmol/mmol The use of extra-corporeal shock wave lithotripsy may be adult <0.04 mmol/mmol an available option in selected patients but the presence L-Glycerate: of nephrocalcinosis may be responsible for parenchymal <0.03 mmol/mmol creatinine damage. Bilateral nephrectomy is recommended in most pa- Plasma Oxalate child <7.4 µmol/l tients on renal replacement therapy in order to limit the risk adult <5.4 µmol/l of infection, obstruction and passage of stones. Oxalate: child <0.19 µmol/µmol creatinine adult <0.06 µmol/µmol Renal Replacement Therapy Conversion factors: oxalate (COOH-COOH) 1 mmol = 90 mg;

Dialysis. Conventional dialysis is unsuitable for patients glycolate (COOH-CH2OH) 1 mmol = 76 mg. who have reached ESRD because it cannot clear sufficient 544 Chapter 43 · Primary Hyperoxalurias

vigorous pre- and postoperative dialysis [24]; however, liv- Post-transplantation Reversal of Renal and Extra-renal In- ing donors should be avoided because the overall results are volvement. Deposits of calcium oxalate in tissues can be poor [23, 25]. Isolated kidney transplantation may be re- remobilized according to the accessibility of oxalate burden garded as a temporary solution in some countries before to the blood stream. After combined transplantation, Pox managing the patient in a specialized center for further returns to normal before urine oxalate does, and oxaluria combined liver-kidney procedure. can remain elevated as long as several months [8, 24, 25]. Independent of initial pyridoxine response, it is recom- Therefore there is still a risk of recurrent nephrocalcinosis or mended to check it again following isolated renal transplan- renal calculi that might jeopardize graft function. Glycolate, tation [24]. which is soluble and does not accumulate, is excreted in nor- mal amounts immediately after liver transplantation. Enzyme Replacement Therapy Thus, independent of the transplantation strategy, the Ideally, any kind of transplantation should precede ad- kidney must be protected against the damage that can be vanced systemic oxalate storage [1, 26]. Further assessment induced by heavy oxalate load suddenly released from tis- of the oxalate burden needs therefore to be predicted by sues. Forced fluid intake (3-5 l/1.73 m2 per day) supported monitoring sequential GFR, Pox (. Table 43.1), calcium by diuretics and the use of crystallization inhibitors is the oxalate saturation and systemic involvement (bone min- most important approach. Pox, crystalluria and calcium eral density, bone histology) [1, 27, 28]. oxalate saturation are helpful tools in renal management after combined liver-kidney transplantation [22, 28, 30]. Rationale for Liver Transplantation. Since the liver is the The benefit of daily high-efficiency (pre-) post-transplant only organ responsible for glyoxylate detoxification by hemodialysis is still debated; it will provide a rapid drop in AGT, the excessive production of oxalate will continue as Pox but also an increased risk of urine calcium-oxalate su- long as the native liver is left in place. Therefore any form persaturation and therefore should be limited to patients of enzyme replacement will succeed only when the defi- with significant systemic involvement [1, 28, 30]. cient host liver has been removed. Liver transplantation Combined transplantation should be planned when the will supply the missing enzyme in the correct organ (liver), GFR ranges between 20 and 40 ml/min per 1.73 m2 because, cell (hepatocyte) and intracellular compartment (per- at this level, oxalate retention increases rapidly [26, 29]. In X oxisome). The ultimate goal of organ replacement is to patients with ESRD, vigorous hemodialysis should be start- change a positive whole-body accretion rate into a negative ed and urgent liver-kidney transplantation should be per- one by reducing endogenous oxalate synthesis and provid- formed. Even at these late stages, damaged organs, such as ing good oxalate clearance via either native or transplanted the skeleton or the heart, do benefit from enzyme replace- kidney. ment [30], which results in an appreciable improvement in quality of life. Combined Liver-Kidney Transplantation. In Europe, 8 to 10 combined liver-kidney transplantations per year have Donors for Combined Liver-Kidney Transplantation. The been reported; the results are encouraging, as patient sur- type of donor -cadaver or living- depends mainly on the vival approximates 80% at 5 years and 65–70% at 10 years physician and the country where the patient is treated [25]. Comparable results have been reported from the Unit- [3, 31, 32]. According to the timing of transplantation, a ed States Renal Data System, with a 76% death-censored living donor may be considered because of the restricted graft survival at 8 years post transplantation [23]. Such a number of potential biorgan deceased donors. A living do- strategy can be successfully proposed to infants with PH1 nor can be proposed in a preemptive procedure using either [4]. In addition, despite the potential risks for the grafted isolated liver or synchronous liver-kidney transplantation. kidney due to oxalate release from the body stores, kidney In patients with ESRD and systemic involvement, a meta- survival is about 95% three years post-transplantation and chronous transplantation procedure might be an option the GFR ranges between 40 and 60 ml/min per 1.73 m2 after since first-step liver transplantation will then allow oxalate 5 to 10 years [25, 26]. clearance by vigorous hemodialysis before considering fur- ther kidney transplantation from the same (living) donor. Isolated liver transplantation might be the first-choice treatment in selected patients before advanced chronic Management of Pregnancy renal failure has occurred, i.e. at a GFR between 60 and There is limited information about outcomes and complica- 40 ml/min/1.73 m2 [29]. Such a strategy has a strong ration- tions of pregnancy in women with PH. In a recent paper ale but raises ethical controversies. Around 25 patients have including 26 pregnancies in 11 patients with PH1 [33], out- received an isolated liver transplant without uniformly ac- comes were: 19 term infants, 2 preterm infants, 3 miscar- cepted guidelines, since the course of the disease is unpre- riages, 1 stillbirth and 1 abortion. No maternal complica- dictable and a sustained improvement can follow a phase of tions were reported in half of the pregnancies; in the remain- rapid decrease in GFR [26, 29]. ing ones, the most common problems were hypertension, 545 43 References

and stone-associated symptoms. 43.2.5 Treatment and Prognosis Only one patient experienced a loss of renal function. Most infants had no complications. The overall long-term prognosis is better than for PH1. ESRD occurs in 12% of patients, between 23 and 50 years Future Trends of age. As in PH1, supportive treatment includes high Although gene therapy has been advocated, many years of fluid intake, crystallization inhibitors and prevention of research will be required before considering its potential complications. Kidney transplantation has been performed use [8]. Different AGT crystal forms have been recently in some patients, often leading to recurrence including obtained for some polymorphic variants, and aminoacid hyperoxaluria and L-glycerate excretion [37]. Liver trans- changes found in these crystals may affect AGT stability plantation has therefore been suggested, but more data [34]. A better understanding of such changes will allow de- are needed concerning the tissue distribution of the de- signing pharmacological agents that will stabilize AGT such ficient enzyme and the biochemical impact of hepatic as chemical chaperones without the need for organ trans- GR/HPR deficiency before such a strategy can be recom- plantation [Danpure, personal communication]. mended. Fourteen pregnancies have been reported in 5 patients with PH2 [33]: 11 led to term infants, 1 to a preterm infant, 43.2 Primary Hyperoxaluria Type 2 1 to stillbirth and 1 to abortion. There were no maternal complications in 6 pregnancies but 2 had hypertension, 2 43.2.1 Clinical Presentation experienced urinary tract infections, and 2 had stone prob- lems. Ten infants had no significant complications; others PH2 has been documented in less than 50 patients but there suffered from pulmonary complications (1), cerebral palsy are some unreported cases. Median age at initial symptoms (1) or developmental delay (1). is 1 to 2 years, and the classical presentation is urolithiasis but stone-forming activity is lower than in PH1 [21]. GFR is usually maintained during childhood and systemic in- 43.3 Non-Type 1 Non-Type 2 Primary volvement is exceptional. Hyperoxaluria

There are some isolated reports of PH without either AGT 43.2.2 Metabolic Derangement or GR/HPR deficiency and of PH with hyperglycoluria in the absence of AGT deficiency [14]. It is therefore likely that PH2 is characterized by the absence of an enzyme with gly- there is at least another form of PH yet to be explained. oxylate reductase (GR), hydroxypyruvate reductase (HPR), and D-glycerate-dehydrogenase activities (. Fig. 43.1) [16]. GR plays a role in the reduction of cytosolic glyoxylate and References has a predominant hepatic distribution [16]. 1. Cochat P, Collard LBDE (2004) Primary hyperoxalurias. In: Avner ED, Harmon WE, Niaudet P (eds) Pediatric nephrology, 5th edn. Lip- 43.2.3 Genetics pincott Williams & Wilkins, Baltimore, pp 807-816 2. Cao LC, Honeyman TW, Cooney R et al (2004) Mitochondrial dysfunction is a primary event in renal cell oxalate toxicity. Kidney There is evidence for autosomal recessive transmission and Int 66:1890-1900 the gene encoding the enzyme GR/HPR (GRHPR) has been 3. Cochat P, Koch Nogueira PC, Mahmoud AM et al (1999) Primary located on chromosome 9cen [35]. Several missense, non- hyperoxaluria in infants: medical, ethical and economic issues. J Pediatr 135:746-750 sense, and deletion mutations have been identified [16]. 4. Millan MT, Berquist WE, So SK et al (2003) One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: 43.2.4 Diagnosis a single-center experience. Transplantation 76:1458-1463 5. Monico CG, Wilson DM, Bergert JH, Milliner DS (1999) Renal oxalate handling and plasma oxalate concentration in patients with chron- The biochemical hallmark is the increased urinary excre- ic renal insufficiency and in patients with primary hyperoxaluria. J tion of L-glycerate (. Table 43.1) but the definitive diagnosis Am Soc Nephrol 10:82A requires measurement of GR activity in a liver biopsy as 6. Diaz C, Catalinas FD, de Alvaro F et al (2004) Long daily hemodialy- some PH2 patients have normal L-glycericaciduria [36]. sis sessions correct systemic complications of oxalosis prior to com- However, in the presence of hyperoxaluria without hyperg- bined liver-kidney transplantation : case report. Ther Apher Dial 8:52-55 lycoluria, a diagnosis of PH2 should be considered and 7. Fargue S, Chevalier-Prost F, Rolland MO, Cochat P (2002) Diagnosis screening of the most frequent mutation (c.103delG) may of primary hyperoxaluria type 1: a one-centre experience. Pediatr be a first line molecular genetic approach [16]. Nephrol 17:C52 546 Chapter 43 · Primary Hyperoxalurias

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