Hoppe, Bernd

Leumann, Ernst

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Nephrol Dial Transplant (2004) 19: 39–42DOI: 10.1093/ndt/gfg507Child–Adult InterfaceDiagnostic and therapeutic strategies in hyperoxaluria:a plea for early interventionBernd Hoppe1 and Ernst Leumann21University Children’s Hospital, Division of Paediatric Nephrology, University of Cologne, Germany and2University Children’s Hospital, Division of Paediatric Nephrology, Zurich, SwitzerlandKeywords: diagnosis; primary hyperoxaluria; second-ary hyperoxaluria; transplantation; treatmentIntroductionOxalic acid is an end product of human metabolismand does not appear to be needed for any process inthe body. Under normal conditions the daily load ofoxalate deriving from endogenous production andintestinal absorption is fully excreted by the kidneys.Up to a certain extent renal oxalate excretion may evenkeep pace with an elevated oxalate load, yet at theexpense of hyperoxaluria, a major risk factor forrecurrent nephrolithiasis and nephrocalcinosis [1,2].Unfortunately, hyperoxaluria is all too often over-looked at this stage. The situation becomes far moreserious if renal function is impaired (e.g. fromcomplications of hyperoxaluria): the amount of oxalateexcreted in the urine will no longer match its produc-tion and absorption, resulting in progressive oxalateretention with renal and extrarenal deposition ofcalcium oxalate, i.e. systemic oxalosis [3]. In a recentsurvey from the US 30% of patients with primaryhyperoxaluria (PH) were only diagnosed after havingreached end-stage renal failure (ESRF [4]). Latediagnosis is a particular problem in adult patients. Ina recent Dutch study, 59% of those patients older than18 years had already reached ESRF at the time ofdiagnosis of PH I [5].Two forms of autosomal-recessive inherited PHshave been characterized at the molecular level, bothbeing due to defects of glyoxylate metabolism [6–8].One or several other types of PH are likely to exist, andthere is a certain overlap with severe forms of secondaryhyperoxaluria [9,10].DiagnosisThe hallmark of type I and II PH is a strongly eleva-ted urinary excretion of oxalate (>1mmol/1.73m2BSA/day, normal <0.5) [1]. Urinary oxalate excre-tion in secondary hyperoxaluria is usually <1.0mmol/1.73m2 BSA/day [2] (Figure 1). Urinary oxalate overcreatinine ratios may be used for screening in childrenas long as age-speciﬁc normal values (for age <2 years,<300; for age 2–5 years, <130; for age 5–15 years,<70 and for age >16 years, <40mmol/mol) are athand [11]. However, the ratios need to be conﬁrmed bycomplete urine collection. Urinary glycolate excretionis elevated in most patients with PH I, whereas urinaryL-glyceric acid excretion is increased in nearly allpatients with PH II. Hence, isolated hyperoxaluriadoes not exclude with certainty either type of PH.On the other hand, hyperoxaluria plus elevated excre-tion of either glycolate or L-glyceric acid is a strongargument but no proof for this diagnosis (PH I or PHII) [9,10].Caution is needed in the interpretation of urinaryvalues in recurrent stone formers who are not stone freeat the time of urine collection, as calcium and oxalateare deposited continuously, leading to ongoing stonegrowth and hence to a lower urinary excretion [12].On the other hand, a high oxalate diet (e.g. spinach,rhubarb juice, etc.) on the day of urine collection mustbe avoided, as it would deﬁnitively increase the urinaryoxalate levels.The ﬁnding of pure CaOxmono-hydrate (whewellite)stones is a hint to the diagnosis of PH. Stones ofpatients with secondary hyperoxaluria are usuallymixed (whewellite and weddellite) [10,13].Values of urinary oxalate are falsely low in patientswith renal insufﬁciency because of oxalate retentionand systemic deposition as calcium oxalate, henceCorrespondence and offprint requests to: Bernd Hoppe, MD,University Children’s Hospital, Division of Paediatric Nephrology,Josef-Stelzmann Strasse 9, D-50931 Cologne, Germany. Email:bernd.hoppe@medizin.uni-koeln.deNephrol Dial Transplant Vol. 19 No. 1  ERA–EDTA 2003; all rights reservedhyperoxaluria may be missed. Determination of plasmaoxalate (POx) can help in this situation. Normal levels ofPOx range from 0.5 to 7.5 mmol/l depending on themethod used [1,14], with 10 mmol/l being the uppercut-off point in our lab. The increase of POx is inverselycorrelated with the fall of GFR, being signiﬁcantlyhigher in PH patients, compared with non-PH patientsin renal insufﬁciency [15].Data of urinary oxalate in ESRF cannot be used incontrast to plasma levels of oxalate and glycolate[16]. Patients with PH have signiﬁcantly higher POxlevels (>80 mmol/l) than non-PH patients in ESRF(<60 mmol/l) [17]. Plasma glycolate levels are signiﬁ-cantly elevated in PH I patients only once they are onrenal replacement therapy [16]. The ﬁnding of bire-fringent CaOx crystals at a bone or kidney biopsy isstrongly suggestive of PH, and an eye groundexamination showing crystal retinopathy is virtuallydiagnostic [1].Liver biopsy for enzymatic analysis is needed fordeﬁnitive diagnosis if liver transplantation is con-sidered, unless the genotype is known or diagnosishas been conﬁrmed in a sibling. DNA analysis asa diagnostic procedure is not a standard techniqueexcept in populations with a high frequency of a speciﬁcmutation [1,18].If these diagnostic procedures do not yield adeﬁnitive diagnosis, further evaluation is recommendedbefore speciﬁc therapy is started. Another recentlyreported cause of signiﬁcant secondary hyperoxaluria isthe absence of oxalate degrading bacteria such asOxalobacter formigenes and, allegedly, other species(Enterococcus faecalis, Eubacterium lentum and lacticacid bacteria) in the gut [19–21]. The obligate anaerobebacterium O.formigenes degrades oxalate to formiate,which is further metabolized and excreted via the faeces[2,19]. It is found in the intestinal tract in the majorityof the adult population (70–80%) and protects themfrom increased intestinal oxalate absorption andensuing hyperoxaluria. Identiﬁcation of Oxalobacterin stool samples is possible with the PCR technique.Recurrent calcium oxalate stone formers and patientswith malabsorption syndromes or patients with hyper-oxaluria of unknown origin often lack Oxalobacter.This might be due to antibiotic treatment (e.g. inpatients with cystic ﬁbrosis), or to speciﬁc therapy ofthe underlying disease (e.g. in Crohn’s disease) [2,22].Increased intestinal oxalate absorption can be assessedby an absorption test using [13C2]oxalate [23]. It helpsto identify hyperabsorbers, who need speciﬁc therapy(e.g. low oxalate, high calcium diet), and to differentiatebetween primary and secondary forms of hyperoxa-luria. It is easy to perform and without risks, as theisotope used is stable.Conservative treatmentMeasures to lower the oxalate loadPrimary hyperoxaluria. Pyridoxal phosphate is anessential cofactor of AGT and pharmacological dosesof pyridoxine may signiﬁcantly reduce hyperoxaluria.About one-third of PH I patients are pyridoxinesensitive [1]. Pyridoxine is started with 5mg/kg bodyweight/day and is stepwise increased up to 20mg/kgday, in order to exclude or demonstrate pyridoxineresponsiveness (>30% reduction). A trial over somemonths is warranted in all PH I patients.Secondary hyperoxaluria. A dietary advice is neces-sary (high calcium, low oxalate diet). The use of oxalatedegrading bacteria like Oxalobacter to reduce theamount of oxalate available for intestinal absorptioncould become an option (perhaps even in the primaryform of hyperoxaluria as an additional measure)[24,25]. Sidhu et al. [26] reported successful andsafe recolonization of O.formigenes in rats, leading toa reduction of urinary oxalate excretion. CampieriFig. 1. Pathways of primary and secondary hyperoxaluria.40 B. Hoppe and E. Leumannet al. [21] treated ﬁve hyperoxaluric patients with apreparation of lactic acid bacteria (Oxadrop) andobserved a signiﬁcant and persistent reduction inurinary oxalate excretion over time.Measures to increase the urinary solubility ofcalcium oxalateMost important is a high ﬂuid intake (3–4 l/day)accompanied by the administration of either alkali(Kþ/Naþ)–citrate [0.3–0.5meq (0.1–0.15 g)/kg bodyweight/day] or orthophosphate (20–60mg/kg bodyweight/day) [1].DialysisNo form of dialysis, not even the combination ofroutine haemo- and peritoneal dialysis is able to keepup with the endogenously produced oxalate, let aloneto reduce the body oxalate burden [27,28]. In fact, theweekly oxalate elimination via haemo- or peritonealdialysis (6–9mmol/week/1.73m2 BSA) only equalsthe endogenous oxalate production of 2–3 days [27].Hence, intensiﬁed haemodialysis with ﬁve to sixsessions of 5 h/week and additionally nightly peritonealdialysis may be considered until transplantation isperformed. The higher the systemic oxalate burden themore oxalate needs to be excreted after transplantation,which further increases the risk of recurrence in thetransplant. Apart from young age (<5 years), a longperiod on dialysis (>2 years) inevitably leading tomassive systemic oxalate deposition is a speciﬁc risk fortransplantation [9,29]. Hence, the dialysis period has tobe kept as short as possible.Transplantation in primary hyperoxaluriaIsolated kidney transplantation is an option only for theminority of patients responding well to pyridoxine[1,30], and, perhaps, for patients with late onset ofESRF (e.g. age >50 years). As a result of the high riskof recurrence, combined liver/kidney transplantation isthe treatment modality of choice in Europe. Isolatedkidney transplantation is, however, still favoured in theUSA, preferably from living related donors [30]. Themedium term results are acceptable with actuarialsurvival of 84% for patients and 51% for grafts after6 years; however, graft survival at 10 years is only35% [30].As the metabolic defect in PH I is conﬁned to theliver, combined liver/kidney transplantation will cure theenzyme defect. Total hepatectomy of the patient’s ownand otherwise normal liver is necessary. Auxiliary livertransplantation is no option, as the oxalate over-production by the patient’s own liver would keepthe process ongoing [1]. More than 100 combinedliver/kidney transplantations have been performed inEurope since 1984 with an actuarial survival at 5 years(98 grafts in 93 patients) being 80% for patients and71% for liver grafts. Renal function has remainedstable with creatinine clearance of 40–60ml/min1.73m2 BSA after 5 years [1,29].Additional haemodialysis or haemoﬁltration aftertransplantation is only required if (renal) graft functionis inadequate. A steady high ﬂuid intake (3–4 l/day) andmedication to increase the urinary solubility of oxalateare needed during the ﬁrst months because of the slowmobilization of the accumulated body oxalate [1]. Notonly urinary oxalate excretion but also plasma oxalateand plasma calcium oxalate saturation remain elevatedfor several months or even years after successfulcombined liver/kidney transplantation [1,15].Pre-emptive (isolated) liver transplantation is anoption with the aim of avoiding ESRF [31]. However,as liver transplantation is not harmless and the optimaltiming of transplantation is difﬁcult to determine due tothe unpredictable course of the disease, it is still not agenerally accepted method for patients with PH I.Nevertheless, several patients with PH I not in renalfailure have been treated this way with reasonableresults [31]. Liver transplantation needs to be per-formed as long as kidney function is still appropriate(GFR >40ml/min, or even 50–70ml/min) [1,18].OutlookThe time lag between the ﬁrst symptom and thediagnosis often is far too long. Hence, the level ofsuspicion needs to be lowered and the diagnosticapproach must be improved. Urinary oxalate excretionhas to be assessed in every patient with calcium oxalateurolithiasis or nephrocalcinosis, and kidney stonesrequire appropriate analysis. Waiting for the nextlithotripsy session is by no means a preventive measure!Various therapeutic approaches are available, theultimate goal being to prevent renal failure. AlthoughPH type I would be a good candidate for gene therapyit is not yet applicable. Perhaps enzyme therapythroughO.formigeneswill become a therapeutic option.Note: early diagnosis and treatment are mandatoryin patients with PH to prevent a disastrous clinicalcourse.Conﬂict of interest statement. B. Hoppe receives grant money fromIxion Biotechnology Inc., Gainseville, FL, USA for oxalosacteresearch.References1. Leumann E, Hoppe B. The primary hyperoxalurias. J Am SocNephrol 2001; 12: 1986–19932. Hoppe B, Leumann E, von Unruh G, Laube N, Hesse A.Diagnostic and therapeutic approaches in patients withsecondary hyperoxaluria. Front Biosci 2003; 8: e437–4433. Wichmann G, Passauer J, Fischer R, Weise M, Gross P.A young patient with end-stage renal disease, dyspnoea,weakness, peripheral neuropathy and an unsuspected under-lying disease. Nephrol Dial Transplant 2003; 18: 1670–16724. Hoppe B, Langman C. A United States survey on diagnosis,treatment and outcome of patients with primary hyperoxaluria.Pediatr Nephrol 2003; 18: 986–991Diagnostic and therapeutic strategies in hyperoxaluria 415. Van Woerden CS, Groothoff JW, Wanders RJ, Davin JC,Wijburg FA. Primary hyperoxaluria type 1 in the Netherlands:prevalence and outcome. Nephrol Dial Transplant 2003; 18:273–2796. Danpure CJ, Jennings PR. 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Diagnostic and therapeutic strategies in hyperoxaluria: a plea for early intervention

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