|Year : 2004 | Volume
| Issue : 1 | Page : 41-49
Sally Ann Johnson, Sally-Anne Hulton
Department of Nephrology, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, United Kingdom
Click here for correspondence address and email
|How to cite this article:|
Johnson SA, Hulton SA. Primary Hyperoxaluria. Saudi J Kidney Dis Transpl 2004;15:41-9
| Introduction|| |
The primary hyperoxalurias are rare inborn errors of metabolism associated with increased endogenous oxalate synthesis. Secondary hyperoxaluria is attributed to increased intestinal absorption or excessive dietary intake of oxalate. The primary hyperoxalurias are generally divided into two types, primary hyperoxaluria type 1 (PH1) occurring more commonly, and the rarer form, primary hyperoxaluria type 2 (PH2). Oxalate is an end product of intermediary cell metabolism and the kidney is the only route of its elimination from the body [Figure - 1]. In these disorders the calcium oxalate activity product is markedly raised which leads to calcium oxalate urinary stones and nephrocalcinosis, which in turn leads to progressive loss of renal function. Following the onset of renal failure and the consequent failure of excretion of oxalate, there is rapid development of systemic oxalosis with deposition of oxalate crystals in almost any site throughout the body.
Although the primary hyperoxalurias are rare disorders they are of considerable clinical importance in that they account for 1.6 % of patients starting renal replacement therapy before the age of 15 in a European survey dating from 1987 to 1991.  In Tunisia, where the frequency of parental consanguinity is high, the disorders are responsible for 17% of children with chronic renal failure.  Primary hyperoxaluria accounts for 7 to 14 % of children with nephrocalcinosis. 
Although most patients with primary hyperoxaluria present with renal calculi in childhood or adolescence, the clinical presentation can range from death in infancy in PH1 to asymptomatic cases in adulthood in both PH1 and PH2.  This phenotypic diversity, together with the rarity of the disease may account for the delay in diagnosis commonly noted in these patients.
| Enzymology|| |
PH1 is caused by a deficiency and/or defect of the enzyme alanine glyoxylate aminotransferase (AGT).  AGT activity can be assayed from material obtained by percutaneous liver biopsy. PH1 is heterogeneous at the enzymological level, with respect to both AGT catalytic activity and AGT immunoreactivity. The analysis of hepatic AGT levels identifies 3 main categories of AGT:
- Absence of both immunoreactive and catalytically active AGT (CRN-/ENZ-)
- Presence of immunoreactive AGT but absence of catalytically active AGT (CRN+/ENZ-).
- The presence of both immunoreactive and catalytically active AGT (CRN+ /ENZ+). 
In most healthy subjects AGT is localised entirely in the peroxisome of the liver parenchymal cells [Figure - 1]. However, in a minority of people a small portion of the AGT (< 5%) is also located in the mitochondria.  In most CRN+/ENZ- PH1 patients the catalytically inactive AGT is found entirely in the peroxisome. However, in the ENZ+/CRN+ patients most of the AGT (about 90%) is localised in the mitochondria and only 10% localised in the peroxisome. Thus these patients have the disease, not because of an overt deficiency of AGT but because their AGT is mistargeted in the wrong subcellular organelle.
PH2 is caused by defects in an enzyme with glyoxylate reductase (GR), hydroxypyruvate reductase (HPR) and D-glycerate dehydrogenase (D-GDH) activity [Figure - 1].  The enzyme functions primarily as a reductase, acting to remove cytosolic glyoxylate, thereby preventing its conversion to oxalate.  As a result of reduced HPR activity, hydroxypyruvate accumulates and is converted to L-glycerate by lactate dehydrogenase. These enzyme defects explain the hallmarks of this condition, namely raised urinary oxalate and Lglycerate. 
| Molecular Genetics|| |
The human AGT gene is located on chromosome 2q37.3.  Over 30 mutations have been identified in the gene encoding AGT (AGXT). Two mutations, G630A and T853C account for approximately 30% of disease alleles in PH1 and are associated with mitochondrial mistargeting and defective peroxisomal uptake of the AGT protein. ,
The gene encoding the defective enzyme in PH2 has been assigned the locus designation GRHPR and has been mapped to chromosomenine. , At least six mutations have been identified, , including missense, nonsense and deletion mutations, allowing molecular diagnostics to be used.
| Pathophysiology|| |
Deficiency of AGT results in accumulation of glyoxylate and subsequent over-production of oxalate and glycolate. Hyperoxaluria and hyperglycolic aciduria are the biochemical hallmarks of PH1. In PH2, deficiency of GRHPR results in accumulation of glyoxylate and L-glycerate, with subsequent conversion of glyoxylate to oxalate. The biochemical hallmarks of PH2 are therefore raised urinary oxalate and L-glycerate.
The kidney, the sole route of oxalate excretion, is the primary target organ of the disease process. Progressive calcium oxalate nephrolithiasis and nephrocalcinosis result in renal failure, which in turn leads to systemic oxalosis, the accumulation of oxalate in the soft tissues and bones. Oxalate is freely filtered in the glomerulus and is both secreted and re-absorbed in the proximal tubule.  In PH1 excessive oxalate is filtered in the glomeruli leading to extremely high oxalate concentrations within the proximal tubular cells. These oxalate levels have a direct toxic effect on renal tubular cells, and may also exert toxic effects on other organs and tissues. ,
Plasma oxalate levels and plasma calcium oxalate saturation values have been studied in PH1 and both are significantly higher in patients with PH1 than in normal individuals. Plasma calcium oxalate supersaturation (plasma CaOx saturation of > 1) with plasma oxalate levels of > 30 µMol, is observed with a GFR of < 45 ml/min/1.73m 2 in contrast to non-PH1 patients for whom supersaturation occurs only with a GFR of < 8 ml/min/1.73m 2 .
Thus calcium oxalate deposition occurs early in these patients who are at risk of systemic calcium oxalate deposition before significant renal impairment occurs. ,,
| Diagnosis|| |
The diagnoses of PH1 and PH2 are often overlooked or must be considered in all patients presenting with renal calculi. Stone analysis that reveals calcium oxalate monohydrate should always prompt further investigations.
Elevated urinary oxalate excretion of > 2 mmol/24 hours/1.73 m 2 (normal < 0.5) should alert the physician to a diagnosis of PH.  Some family studies have demonstrated that some untreated patients with PH1 may have a normal urinary oxalate or only slightly elevated excretion (0.5 to 1.0 mmol/24 hours/1.73 m2). 
Particular attention must be paid to the method of urine collection for oxalate analysis. The patients must not be receiving vitamin C supplements, as this falsely elevates oxalate values. A fresh sample must be collected and sent immediately to the laboratory for analysis, unless the urine is collected in a container acidified with hydrochloric acid (to a PH of < 2.0). Delays will cause false elevation of oxalate concentration by oxidation. A spot urine collection can be used to determine the excretion of oxalate in the urine by comparing it to the concentration of creatinine in the urine. The physician should always consult age related tables for oxalate to creatinine ratios. , Renal failure is associated with oxalate retention and reduced urinary excretion, underlying the need for plasma oxalate in suspected cases. In all suspicious cases plasma oxalate determinations may be helpful. Glycolate levels are elevated in 60% of patients with PH1 and normal values for glycolate do not exclude this diagnosis.
The diagnosis of PH2 can be confirmed by the finding of raised urinary oxalate as in PH1 but must be associated with raised urinary L-glycerate on gas chromatography or mass spectrometry.
Plasma Oxalate Measurement
Plasma oxalate samples need to be transported rapidly to the laboratory for processing in order to avoid falsely elevated results.
A definitive diagnosis of PH1 can be obtained by assessment of AGT activity and immunoreactivity in hepatic tissue. Such confirmation is always required if liver transplantation is being considered, unless a diagnosis has already been established via molecular genetics. The role of liver biopsy in PH2 is debated. , Previously the diagnosis was based solely on the finding of hyperoxaluria and hyperglycericaciduria. However there have been recent descriptions of 2 children with enzymatically proven PH2 without raised L-glycerate excretion.  As genetic analysis is not available for all possible mutations, the analysis of GRHPR activity on liver biopsy may play a role in some cases, particularly those with hyperoxaluria in the absence of urinary Lglycerate.
Patients with PH1 are often compound heterozygotes in which the mutation on the second allele may be unidentified. Pre-natal diagnosis can be performed by linkage analysis using chorionic villous sampling if the family has been demonstrated to be informative for the linkage marker.  Genetic counselling must always take into account the fact that family members carrying identical mutations may exhibit a completely different clinical course and that the relationship between genotype and phenotype has not been adequately established.
As more information regarding the mutations in patients with PH2 is identified, genetic counselling is now available for families for this condition.
| Clinical Manifestations|| |
PH1 displays considerable phenotypic variability within identical genotypes ranging from severe infantile oxalosis and renal failure, to a completely asymptomatic state. Patients with PH 1 typically present with symptoms early in childhood, with the first signs of disease being present in 50% of children under the age of 5 years.  By 25 years of age 90% of patients are symptomatic. Initial symptoms are attributable to calculi in the renal tract and the presentation is often that of renal colic, hematuria or urinary tract infection. Infants with the severe form of the disease present with systemic oxalosis and renal failure. These infants demonstrate diffuse nephrocalcinosis but not urolithiasis. The deposition of calcium oxalate occurs in every tissue in the body except for the liver. Bone oxalate deposition results in extreme bone pain, spontaneous fractures and Erythropoietin resistant anemia. Retinal oxalate deposits can be diagnosed by slit lamp examination and can be used to support a diagnosis. Of particular importance is the deposition of calcium oxalate in the media of arteries, which can result in subsequent ischemia and altered myocardial function. Renal biopsy is not required for diagnostic purposes, but oxalate crystals can be seen on histology when this tissue is available. Clinical manifestations are also variable in PH2, although they may be less severe than PH1.  Approximately 40 cases of PH2 have been described in literature and of these 60% had urolithiasis and 10% had nephrocalcinosis. ,,,,,,,,,
Approximately 15% developed moderate to severe renal impairment, secondary to urolithiasis or nephrocalcinosis, ,,, with half of these patients requiring renal replacement therapy. In a study of 13 children with PH2, 53% developed urolithiasis and the median age at detection of first stone was 3.25 years.  Twenty-three percent developed nephrocalcinosis. In this study a large proportion (8/13) were detected by screening of siblings of affected individuals, and 75% of these children remained unaffected by urolithiasis or nephrocalcinosis at the end of the follow-up period (mean 5.4 years).
Although PH2 appears less severe, the potential for ESRF and systemic oxalosis remains, and this seems to occur in adults rather than children, unlike PH1.
| Management|| |
A high fluid intake is the key recommendation in preventing renal stone formation in both forms of PH (1.5-2L/m 2 per day). As oxalate is produced at a constant rate in primary hyperoxaluria, regardless of the stage of the disease, if the urine is adequately diluted oxalate excretion may be achieved without crystal formation.  Citrate, orthophosphate and magnesium, have been shown to act as inhibitors of calcium oxalate crystallization. By competing with calcium, citrate lowers the ionic calcium concentration and causes a reduction in the saturation of calcium oxalate.  Orthophosphate has been noted to decrease calcium oxalate saturation. 
Pyridoxal phosphate is the co-factor of AGT activity. High doses of pyridoxine have been used in some patients with PH1 to reduce urinary oxalate concentrations with claims of partial or complete responsiveness to this co-factor.  Pyridoxine should be commenced at 5 mg/Kg/day, increasing to 20 mg/Kg/day according to urinary oxalate excretion. This therapy should be continued for at least three months. A response may be noted in approximately one third of patients.  Patients receiving high doses of pyridoxine need to be monitored for peripheral neuropathy, the finding of which necessitates immediate withdrawal of the drug. Pyridoxine has not been shown to affect oxalate levels in PH2. 
Oxalate production is so high in PH that dietary recommendations for avoiding food containing oxalate (for example spinach, beetroot, strawberries, rhubarb and tea) are only of marginal benefit. Individuals who lack the intestinal oxalate degrading bacteria (Oxalobacter formigenes) will demonstrate greater dietary oxalate absorption. 
| Non-conservative Treatment|| |
Neither haemodialysis nor peritoneal dialysis is able to remove effectively the quantity of oxalate that is produced continuously in PH1 patients. Although the oxalate clearance on hemodialysis (approximately 120 ml/min) is greater than that on peritoneal dialysis (approximately 7 ml/min) the weekly oxalate elimination rates are similar for these two modes of therapy.  A combination of therapies, including highflux prolonged dialysis, with or without hemofiltration, has no significant long-term effect on plasma oxalate levels either. Dialysis is therefore reserved for patients who develop ESRF, in both PH1 and PH2.
More recently, two transplantation options have emerged for patients with PH1 in whom conservative management is unsuccessful. Isolated liver transplantation is able to correct the metabolic defect prior to significant renal damage occurring, whereas combined hepatorenal transplantation is required once endstage renal failure has occurred. Previously, isolated renal transplantation was offered for patients in established end-stage renal failure, but this offers only a temporary solution as oxalate deposition will recur in the graft over time. Isolated liver transplantation is an attractive option in cases where the residual renal function is preserved because it corrects the metabolic defect before systemic complications occur. The timing of the preemptive liver transplant remains controversial and as the procedure is invasive the decision to remove the native liver can be particularly difficult as the course of the disease is hard to predict. Five year patient survival following combined hepatorenal transplantation is of the order of 70%.  The outcome for children is much more guarded and mortality for children under the age of 5 undergoing combined transplantation may be as high as 40%, although survival in the 5 to 10 year old children is about 80%. , Combined hepatorenal transplantation has an added immunological advantage that the liver graft may protect the renal graft against rejection. 
Attempts have been made to establish guidelines for transplantation in PH1 based on the glomerulus filtration rate and clinical condition of the patients. Liver-kidney transplantation is recommended when the GFR is between 25 and 40 ml/min/1.73m 2 , particularly if there is rapid deterioration or severe extra renal involvement. Isolated liver transplantation is the preferred option when the GFR is between 40 and 60 ml/min/1.73m 2 and the disease appears to be following an aggressive course. , Nephrocalcinosis implies significant disease in children in PH 1 and this should alert the physician to check carefully for evidence of systemic oxalosis and consider transplantation based on the GFR.  End-stage renal failure with systemic oxalosis is associated with extremely poor quality of life, thus the potential long-term benefits of transplantation are great, even though the morbidity and mortality are high. Both careful consideration of combined hepatorenal transplantation or pre-emptive liver transplantation in selected cases can minimise complications and improve outcome for these children.
Renal transplantation has been used for two patients with ESRF in PH2, although in both reported cases there was significant oxalate deposition in the graft, causing loss of the graft in 1 case.  Liver transplantation has not been explored as PH2 follows a less severe disease course than PH1, compared with PH2, and secondly the enzyme encoded by GRHPR is distributed in leucocytes and renal tissue in addition to the liver.  It is not known whether isolated liver transplant would sufficiently restore GRHPR activity.
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Department of Nephrology, Birmingham Children's Hospital, NHS Trust, Steelhouse Lane, Birmingham, B4 6NH
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