What is new in primary hyperoxaluria?

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(1)2556. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.. 19.. degradation of hyaluronate by synovia from patients with rheumatoid arthritis. J Rheumatol 1995; 22: 400–405 Li M, Rosenfeld L, Vilar RE, Cowman MK. Degradation of hyaluronan by peroxynitrite. Arch Biochem Biophys 1997; 341: 245–250 Ginetzinsky AG. Role of hyaluronidase in the reabsorption of water in renal tubules: the mechanism of action of antidiuretic hormone. Nature 1958; 182: 1218–1219 MacPhee PJ. Estimating rat renal medullary interstitial oncotic pressures and the driving force for fluid uptake into ascending vasa recta. J Physiol (Lond) 1998; 506 (Pt 2): 529–538 Johnsson C, Tufveson G, Wahlberg J, Hallgren R. Experimentally induced warm renal ischemia induces cortical accumulation of hyaluronan in the kidney. Kidney Int 1996; 50: 1224–1229 Wells A, Larsson E, Hanas E et al. Increased hyaluronan in acutely rejecting human kidney grafts. Transplantation 1993; 55: 1346–1349 Sibalic V, Fan X, Loffing J, Wu¨thrich RP. Upregulated renal tubular CD44, hyaluronan and osteopontin in kdkd mice with interstitial nephritis. Nephrol Dial Transplant 1997; 12: 1344–1353 Nishikawa K, Andres G, Bhan AK et al. Hyaluronate is a component of crescents in rat autoimmune glomerulonephritis. Lab Invest 1993; 68: 146–153 Jun Z, Hill PA, Lan HY et al. CD44 and hyaluronan expression in the development of experimental crescentic glomerulonephritis. Clin Exp Immunol 1997; 108: 69–77 Feusi E, Sun LK, Sibalic A, Beck-Schimmer B, Oertli B, Wu¨thrich RP. Enhanced hyaluronan synthesis in the MRL-Faslpr kidney: role of cytokines. Nephron 1999; 83: 66–73 Hallgren R, Engstrom Laurent A, Nisbeth U. Circulating hyaluronate. A potential marker of altered metabolism of the connective tissue in uremia. Nephron 1987; 46: 150–154 Sun LK, Feusi E, Sibalic A et al. Expression profile of hyaluronidase mRNA transcripts in the kidney and in renal cells. Kidney Blood Press Res 1998; 21: 413–418 Oertli B, Fan X, Wu¨thrich RP. Characterisation of CD44-mediated hyaluronan binding by renal tubular epithelial cells. Nephrol Dial Transplant 1998; 13: 271–278 Benz PS, Fan XH, Wu¨thrich RP. Enhanced tubular epithelial CD44 expression in MRL-lpr lupus nephritis. Kidney Int 1996; 50: 156–163 Roy-Chaudhury P, Khong TF, Williams JH et al. CD44 in glomerulonephritis: Expression in human renal biopsies, the Thy 1.1 model, and by cultured mesangial cells. Kidney Int 1996; 50: 272–281 Hallgren R, Gerdin B, Tufveson G. Hyaluronic acid accumulation. Nephrol Dial Transplant (1999) 14: Editorial Comments. 20. 21. 22. 23.. 24.. 25.. 26. 27.. 28.. 29. 30. 31.. 32.. and redistribution in rejecting rat kidney graft. Relationship to the transplantation edema. J Exp Med 1990; 171: 2063–2076 Beck-Schimmer B, Oertli B, Pasch T, Wu¨thrich RP. Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells. J Am Soc Nephrol 1998; 9: 2283–2290 McKee CM, Penno MB, Cowman M et al. Hyaluronan (HA) fragments induce chemokine expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest 1996; 98: 2403–2413 Lake FR, Noble PW, Henson PM, Riches DW. Functional switching of macrophage responses to tumor necrosis factor-a (TNF-a) by interferons. J Clin Invest 1994; 93: 1661–1669 Hodge-Dufour J, Noble PW, Horton MR et al. Induction of IL-12 and chemokines by hyaluronan requires adhesion-dependent priming of resident but not elicited macrophages. J Immunol 1997; 159: 2492–2500 Oertli B, Beck-Schimmer B, Fan X, Wu¨thrich RP. Mechanisms of hyaluronan-induced up-regulation of ICAM-1 and VCAM-1 expression by murine kidney tubular epithelial cells. J Immunol 1998; 161: 3431–3437 Oertli B, Beck-Schimmer B, Sibalic A, Wu¨thrich RP. Crosslinking of CD44 upregulates ICAM-1 and VCAM-1 by a rapid and transcriptionally independent mechanism in renal tubular epithelial cells. J Am Soc Nephrol 1998; 9: 465A Fujii K, Tanaka Y, Hubscher S et al. Cross-linking of CD44 on rheumatoid synovial cells up-regulates VCAM-1. J Immunol 1999; 162: 2391–2398 McKee CM, Lowenstein CJ, Horton MR et al. Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kB-dependent mechanism. J Biol Chem 1997; 272: 8013–8018 Kobayashi H, Sun GW, Terao T. Production of prostanoids via increased cyclo-oxygenase-2 expression in human amnion cells in response to low molecular weight hyaluronic acid fragment. Biochim Biophys Acta 1998; 1425: 369–376 Noble PW, McKee CM, Cowman M, Shin HS. Hyaluronan fragments activate an NF-kB/I-kBa autoregulatory loop in murine macrophages. J Exp Med 1996; 183: 2373–2378 Mikecz K, Brennan FR, Kim JH, Glant TT. Anti-CD44 treatment abrogates tissue oedema and leukocyte infiltration in murine arthritis. Nature Med 1995; 1: 558–563 Knoflach A, Azuma H, Magee C et al. Immunomodulatory functions of low-molecular-weight hyaluronate in an acute rat renal allograft rejection model. J Am Soc Nephrol 1999; 10: 1059–1066 Knoflach A, Magee C, Denton MD et al. Immunomodulatory functions of hyaluronate in the LEW-to-F344 model of chronic cardiac allograft rejection. Transplantation 1999; 67: 909–914. Nephrol Dial Transplant (1999) 14: 2556–2558. What is new in primary hyperoxaluria? Ernst Leumann1 and Bernd Hoppe2 1Nephrology Unit, University Children’s Hospital, Zurich, Switzerland and 2Nephrology Unit, University Children’s Hospital, Cologne, Germany. Introduction Although the majority of renal stones both in children and in adults are formed by calcium oxalate (CaOx), few patients actually suffer from a primary metabolic Correspondence and offprint requests to: Prof. Ernst Leumann, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.. defect leading to excessive endogenous production of oxalate. Nevertheless, there is considerable interest in primary hyperoxaluria (PH )—the prototype and model of hyperoxaluria—since a better understanding of the pathogenic mechanisms is also expected to help the much larger group of patients with urolithiasis not suffering from PH. Two recent symposia (NIH Workshop, 8–9 December 1998, Bethesda, USA and 5th Workshop on PH, 12–13 March 1999, Zurich,.

(2) Nephrol Dial Transplant (1999) 14: Editorial Comments. 2557. Switzerland ) have dealt with these problems [1]. It has become obvious that PH is a highly complex disorder, consisting of two well-described forms (PH1 and PH2) and of further conditions.. the same core obtained by needle biopsy [1 (A 9); 8]. Precise diagnosis is of great importance for prognosis (type of PH ), genetic counselling including prenatal diagnosis, and if liver transplantation is considered.. Toxicity. Primary hyperoxalurias. Oxalate is a useless end-product of metabolism and is normally completely excreted by the kidneys (normal excretion <0.5 mmol (45 mg)/24 h/1.73 m2). Oxalate and calcium oxalate (CaOx) crystals, once believed to be biologically inert, exert toxic effects on renal epithelial cells [1 (A 11,12); 2–4]. These effects are comparable to those resulting from oxidative stress on tissues, because oxalate increases the production of free radicals [2]. The extremely high urinary oxalate concentrations in patients with PH may therefore be harmful. Thus, any increase in oxalate not only has a strong effect on the urinary saturation of CaOx (10 times as much as an equimolar increase of calcium), but in addition may lead to direct tubular damage.. PH1. Intestinal absorption Only 5–10% of the urinary oxalate normally originates from daily nutrition. This fraction is even lower in PH patients, considering their extremely high endogenous oxalate production. However, intestinal absorption might become a relevant factor if it is increased (as is the case in some forms of secondary hyperoxaluria). Absence of the anaerobic intestinal oxalate-degrading bacterium Oxalobacter formigenes (which is found in up to 80% of the normal population) has been shown to be associated with (secondary) hyperoxaluria in patients with cystic fibrosis and in patients with recurrent urolithiasis [1 (A 16); 5]. Another cause of increased intestinal oxalate absorption is calcium restriction, as less calcium is available to bind oxalate and to form (insoluble) CaOx complexes in the gut.. Plasma oxalate and CaOx saturation Plasma oxalate (P ) and plasma CaOx saturation Ox (b ) are increased early in PH patients [6,7]. CaOx Therefore the main purpose of therapy is to lower P Ox and b (to which P is significantly correlated) or CaOx Ox at least to prevent its steady increase. Both parameters are inversely correlated with GFR, hence the risk of systemic CaOx deposition (oxalosis) is increased in renal insufficiency, even before end-stage renal failure ( ESRF ) occurs [6 ].. Liver biopsy Urinary metabolites often are not conclusive for diagnosis of PH1 or PH2. The enzyme defects of PH1 and PH2 can now be determined in hepatic tissue from. PH1—a ‘nephrological liver disease’—is due to a defect or absence of liver-specific peroxisomal alanine:glyoxylate aminotransferase (AGT ), resulting in elevated urinary excretion of oxalate and (in most cases) of glycolate. The AGXT gene is located on chromosome 2q37.3 and spans over 11 exons [9]. Over 25 different mutations have been found so far. Around 30% of patients have the G A mutation, leading to a Gly A 630 170 amino acid substitution, which is mostly associated with a C T polymorphism (Pro Leu). This mutation 154 11 is particularly interesting because it leads to an unparalleled protein trafficking defect in which AGT is mistargeted from peroxisomes to mitochondria. Further studies have yielded insights into some of the fundamental differences in the way proteins are targeted to, and imported into, peroxisomes and mitochondria [9]. Clinically, PH1 is also very heterogeneous, with the spectrum ranging from early ESRF (infantile oxalosis) to occasional kidney stones in adults [1]. The clinical heterogeneity is not sufficiently explained, neither by AGT activity or localization, nor by disease specific genotypes. Even siblings with an identical mutation may have a completely different course of the disease [10]. Diagnosis of PH1 is still being missed or delayed all too often, and figures reported represent a minimum. Data from the UK, Switzerland and France suggest that 1 in 60 000 to 120 000 children suffers from PH1 [1 (A 2); 11]. The disease is far more common in certain countries like Tunisia, where PH1 is the cause of ESRF in 13% of paediatric patients as compared to 0.3% in Europe [1 (A 3,4)]. From Israel, seven distinct mutations (including five novel ones) were reported in eight heavily inbred (Israelı–Arab) families with a high prevalence of the severe infantile form [1 (A 5)]. Therapy of PH1 Generous fluid intake and administration of potassium citrate or phosphate together with pyridoxine (vitamin B ) is still the basis of therapy. Attempts to reduce the 6 glyoxalate or glycolate pool have not yet been successful [1 (A 14)]. There was agreement to define pyridoxine responsiveness as >30% reduction of urinary oxalate excretion from baseline after stepwise increase of daily dosage of pyridoxine (5–10–15–20 mg/kg after several weeks) [1 (A 15)]. Transplantation According to the latest European Oxalosis Registry Report, actuarial patient survival (98 grafts in 93.

(3) 2558. patients) is 80% at 6 years for combined liver/kidney transplantation (with a much poorer outcome for patients <5 years of age) [1 (A 19)]. This treatment modality is at present the method of choice for PH1 patients in ESRF. Isolated kidney transplantation, advocated in the USA [1 (A 21)], may still be an alternative, e.g. in B -responsive patients [7]. No such 6 therapy is available in some developing countries having a high incidence of PH1. Dialysis is no alternative except for a very limited time. Why not perform pre-emptive (isolated) liver transplantation [1 (A 22, 11)]? Thus far, some 10 patients with PH1 not in renal failure have been treated this way with reasonable results. However, some of the patients might have maintained their renal function without intervention. It is impossible to establish guidelines, and it seems unlikely that pre-emptive liver transplantation will become popular in PH1. Prospects of gene therapy Considerable problems need to be overcome. In analogy to auxiliary liver transplantation (which does not work because the diseased liver will continue to produce oxalate in excess), it would require far more than 20 or 30% of liver cells to be transfected—a task impossible to solve with current vector technology [1 (A 1)]. However, the goal is set. PH2 PH2 results from absent glyoxylate reductase (GR) activity (GR also possesses hydroxypyruvate reductase and -glycerate dehydrogenase activity). Much progress has been made in this disease which primarily leads to repeated stone formation and less to nephrocalcinosis and ESRF. The hallmark is the high urinary excretion of oxalate and -glyceric acid. Diagnosis can now be confirmed by measurement of GR activity in liver biopsy [1 (A 9); 8]. The responsible gene has been mapped to the centromeric region of chromosome 9 (probably p11) and contains nine exons [1 (A 7; 12)]. PCR-SSCP and sequence analysis of DNA from four patients of three different families have identified a single nucleotide deletion in exon 2 resulting in a frameshift mutation [1 (A 7)]. PH2 is also underdiagnosed; one-third of paediatric patients with PH in the West Midlands ( UK ) turned out to have PH2 and not PH1 [1 (A 2)].. Atypical PH As it has been the case in other metabolic diseases, the advent of enzyme measurement has demonstrated clearly that PH is heterogeneous: not all patients with PH (i.e. without evidence of secondary hyperoxaluria) can be classified as PH1 or PH2. These patients, observed at different places, had early manifestation of urolithiasis [1 (A 17,18)]. Why not call this condition PH3? There is considerable evidence that this group is heterogeneous and contains further subtypes (PH4,. Nephrol Dial Transplant (1999) 14: Editorial Comments. etc.). The search for the metabolic defect(s) in atypical PH, the term preferred at the Workshop, is ongoing.. Conclusion In conclusion, much progress has been made during recent years, and molecular genetics and enzyme diagnostics have firmly been established in PH1 and PH2. However, considerable effort is necessary to explain the discrepancy between genotype and phenotype in PH1 and to define the underlying metabolic defects of atypical PH. The optimal treatment, especially for patients with PH1 and renal insufficiency remains a matter of debate, and not all agree with early enzyme replacement therapy=pre-emptive liver transplantation. Intensified research in PH will also benefit the large number of patients with secondary hyperoxalurias. No doubt, the 6th PH workshop will be exciting again!. References 1. Abstracts of 5th Workshop on Primary Hyperoxaluria, Kappel/ Zurich, 12–13 March 1999. Nephrol Dial Transplant 1999; 14: 2784–2789 2. Scheid C, Koul H, Hill WA et al. Oxalate toxicity in LLC-PK1 cells: role of free radicals. Kidney Int 1996; 49: 413–419 3. Khan SR, Byer KA, Thamilselvan S et al. Crystal cell interaction and apoptosis in oxalate associated injury of renal epithelial cells. J Am Soc Nephrol 1999: (in press) 4. Lieske JC, Deganello S. Nucleation, adhesion, and internalization of calcium-containing urinary crystals by renal cells. J Am Soc Nephrol 1999: (in press) 5. Sidhu H, Hoppe B, Hesse A et al. Absence of Oxalobacter formigenes in cystic fibrosis patients: a risk factor for hyperoxaluria. Lancet 1998; 352: 1026–1029 6. Hoppe B, Kemper MJ, Bo¨kenkamp A, Langman CB. Plasma calcium-oxalate saturation in children with renal insufficiency and in children with primary hyperoxaluria. Kidney Int 1998; 54: 921–924 7. Marangella M. Transplantation strategies in type 1 primary hyperoxaluria: the issue of pyridoxine responsiveness. Nephrol Dial Transplant 1999; 14: 301–303 8. Giafi C, Rumsby G. Kinetic analysis and tissue distribution of human -glycerate dehydrogenase/glyoxylate reductase and its relevance to the diagnosis of primary hyperoxaluria type 2. Ann Clin Biochem 1998; 35: 104–109 9. Danpure CJ, Purdue PE. Primary hyperoxaluria. In: Scriver CR et al. ed. The Metabolic and Molecular Bases of Inherited Disease, 7th edn. McGraw-Hill, New York, 1995; pp 2385–2424 (8th edn in press) 10. Hoppe B, Danpure CJ, Rumsby G et al. A vertical (pseudodominant) pattern of inheritance in the autosomal recessive disease primary hyperoxaluria type I. Lack of relationship between genotype, enzymic phenotype and disease severity. Am J Kidney Dis 1997; 29(1): 36–44 11. Cochat P. Nephrology forum: primary hyperoxaluria type 1. Kidney Int 1999; 55: 2533–2547 12. Cramer SD, Ferree PM, Lin K, Milliner DS, Holmes RP. The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria Type II. Hum Mol Genet 1999; 8: 2063–2069. Editor’s note Please see also the Fifth Workshop on Primary Hyperoxaluria Abstracts (pp. 2784–2789 in this issue)..

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