Oxalate is derived from endogenous production following the metabolism of glyoxylate within the body as well as from the diet, and is excreted by the kidney. Hyperoxaluria can therefore occur due to hyperabsorption of ingested oxalate, as seen in patients with malabsorption e.g. ulcerative colitis or Crohn’s disease (secondary hyperoxaluria). It can also occur as a result of derangement of the normal metabolic pathways (primary hyperoxaluria, PH).
The primary hyperoxalurias are autosomal recessive disorders of which three have been described at the molecular level (Cochat & Rumsby, 2013).
- Primary hyperoxaluriatype 1 (PH1) is caused by mutations in AGXT which result in dysfunction of the vitamin B6 (pyridoxine) dependent liver specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT) (Purdue, Takada & Danpure, 1990)
- Primary hyperoxaluriatype 2 (PH2) arises from mutations in GRHPR with subsequent dysfunction of the enzyme glyoxylate/hydroxypyruvate reductase (GRHPR) (Cregeen et al, 2003)
- Primary hyperoxaluriatype 3 (PH3) arises from mutations in HOGA1 which is encodes the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (Belostotsky et al, 2010).
As calcium oxalate is poorly soluble, crystals form in the lumen of the renal tubules. These crystals adhere to the tubular epithelium and are internalised into the cells with subsequent extrusion into the interstitial region where they cause an inflammatory reaction, and subsequent nephrocalcinosis. Calculi will also form in the kidney leading to renal damage.
The prevalence of PH is unclear. PH1, the most common of the disorders, has been estimated to have a prevalence of 1-3 per million but it is highly likely that this is an underestimate of the disease.
The primary hyperoxalurias show considerable genetic and phenotypic heterogeneity and can present in the following forms:
- Infantile acute renal failure/metabolic acidosis
- Infantile presentation with faltering growth, early nephrocalcinosis and rapid progression to end stage renal failure
- Occasional passage of renal stones
- Recurrent urolithiasis
- Recurrent urolithiasis with the development of nephrocalcinosis and eventual progressive renal failure
Figure One shows the recommended pathway for urine oxalate testing.
Figure One: Urine oxalate investigation pathway
Sample required: Urine collected into acid to aid solubilisation and to prevent the conversion of ascorbate to oxalate (random or 24h).
Urine glycolate, glycerate and hydroxyoxoglutarate
These can be analysed on the same urine sample. Glycolate indicates PH1, glycerate PH2, and hydroxyoxoglutarate PH3. These tests are not diagnostic however, and their absence cannot definitively exclude the disorders.
Plasma oxalate measurement should be reserved for those patients with significant renal impairment only as it remains relatively normal until a decline in the GFR has occurred. Remember that plasma oxalate is raised in end stage renal failure from many causes other than PH due to inadequate renal excretion.
Sample required: EDTA, plasma separated and frozen promptly (ideally within two hours).
Results need to be interpreted with clinical symptoms. Note there is no simple cut-off for primary vs secondary disease.
Genetic testing is required to confirm the diagnosis as well as to give an indication of prognosis. Sibling and family screening is particularly beneficial and can identify asymptomatic cases which can allow the institution of appropriate therapy before symptoms arise, and prevent decline in renal function accordingly (Rumsby, 2005).
Testing is available for all three genes: AGXT, GRHPR and HOGA1.
Sample required: EDTA whole blood.
The severity of disease, particularly of PH1 means that there is a requirement for prenatal diagnosis
Sample required: Chorionic villus biopsy taken at 10-12 weeks gestation.
The key aims of therapy for all forms of PH are to prevent systemic oxalate deposition with a high fluid intake accompanied by the administration of crystallisation inhibitors. The recommendations for treatment (Cochat et al, 2012) are as follows:
- High fluid intake is mandatory, at least 3 litres/m2/24 hours. This may require the placement of a nasogastric or gastrostomy feeding tube in infants in order to guarantee adequate hydration.
- Oral potassium citrate at a dose of 0.1 – 15 g/kg body weight per day (0.3 – 0.5 mmols/kg/day) to inhibit calcium oxalate crystallisation.
- The administration of Pyridoxine to any patient with proven PH1 starting at a dose of 5 mg/kg/day up to 20 mg/kg/day with the intention of decreasing the urine oxalate excretion by at least 30%. Vitamin B6 is a co-factor for AGT and the administration of pyridoxine has been associated with a decrease in urine oxalate in about 30% of PH1 patients.
Dietary restriction of oxalate is of limited use as the main source of oxalate is endogenous (Sikora, 2008). Some experts recommend avoiding oxalate rich foods in the diet such as dark chocolate, strawberries, spinach and tea on a precautionary principle. Calcium intake should be normal but excessive intake of vitamin C and vitamin D should be avoided (Hoppe et al, 2011; Milliner, 2006).
Management of Urolithiasis
Surgical intervention in the management of uncomplicated urolithiasis in PH patients should be limited. ESWL has now been superseded by endoscopic stone removal such as semi rigid ureterorenoscopy, flexible ureterorenoscopy, and percutaneous nephrolithotomy (Türk et al, 2011; Straub, Gschwend & Zorn, 2010).
Oxalate is generated at a rate of 4-7 mmol/1.73 m2/day in contrast with clearance via conventional dialysis at a rate of 1-4 mmol/1.73 m2/day, resulting in uncontrolled tissue accretion. Oxalate clearance on haemodialysis is greater than on peritoneal dialysis (120 ml/min on haemodialysis compared to 7 ml/min on peritoneal dialysis). Thus standard haemodialysis programmes will result in a weekly clearance of oxalate of 6-9 mmol/1.73 m2/week which is equivalent to 2-3 days of endogenous production of oxalate.
Thus a combination of modalities, with intermittent daily haemodialysis and overnight peritoneal dialysis, enhances the overall clearance of oxalate and attempts to reduce the rebound which occurs after haemodialysis (Hutchinson et al, 2011). These combination therapies with the use of high flux dialysers or long episodes of haemofiltration have all been advocated to improve oxalate removal (Illies et al, 2006; Hoppe et al, 1996). The aim is to prevent the requirement for dialysis and to anticipate impairment in renal function with strategic planning for organ transplantation.
When the GFR falls below 60 ml/min/1.73 m2 assessment for transplantation should take place, initially with isolated liver transplantation being advised if the GFR continues to fall progressively below 60 ml/min/1.73 m2 in patients with PH1. The liver is the only organ responsible for glyoxylate detoxification through the enzyme AGT. Thus liver transplantation is a cure for PH1 but the native liver must be removed in order to avoid excessive oxalate production continuing (Perera et al, 2011; Kemper et al, 1998; Cochat, Fargue & Harambat, 2010).
Combined hepato renal transplantation must be considered when the GFR falls below 40 mls/min/1.73 m2 as there is a dramatic decrease in excretion of oxalate, with increase in plasma oxalate levels, resulting in systemic deposition of calcium oxalate in the heart (cardiomyopathy and conduction defects), vessel walls, skin (ulcerating lesions), nerves (peripheral neuropathy, mono neuritis multiplex), retina and joints (sinovitis). The hepato renal transplantation can be done simultaneously with excellent success even in small infants. A sequential procedure involving hepatic transplantation first, followed by a period of dialysis, with subsequent renal transplantation months later may be considered more appropriate in certain situations (Ellis et al, 2001). This type of approach can be useful if living related donors for split liver or kidney donation are being considered by relatives.
The overall long-term prognosis for patients with PH2 is unclear. It was originally considered to have a more benign course than PH1 with the majority of patients presenting with urolithiasis, but decline in renal function is probably more common than initially considered. Nephrocalcinosis is less common but can occur in childhood and adult life (Johnson et al, 2002). End stage renal failure tends to occur over 25 years of age. The supportive management is the same as for PH1 but there is no rationale for the use of vitamin B6. Renal transplantation has been performed in some of these patients but the majority will have a recurrence of their condition in the transplanted kidney. Success with hepatic transplantation has not been reported.
The principles of management are the same, but in addition a role of a vegetarian diet to reduce dietary hydroxyproline is being considered. At the present time, no PH3 patient has been found in renal failure (Belostotsky et al, 2010).
The Hyperoxaluria Rare Disease Group (RDG) is working with international partners with the aim of finding new and improved treatments, and to empower patients. A first step is to compare the symptoms and genetic markers of PH. To do this the RDG is registering patients with this condition into two research registries. The first is the UK-based National Renal Rare Disease Registry (RaDaR) which will be used to find suitable participants for future research trials into the effectiveness of new treatments.
The second is the International Hyperoxaluria Registry run by Oxal Europe, the European Hyperoxaluria Consortium, which aims to compile a global registry of Hyperoxaluria patients. Patient information in both registries is anonymous and cannot be linked to individuals.
There are trials for adult patients with primary hyperoxaluria types 1, 2 & 3 and enteric hyperoxaluria, which are all recruiting or about to start. Here are the key inclusion criteria:
- Adult patient with PH1: eGFR>45 and 24h U Oxalate >700 umol/24h
- Adult patient with PH1 or 2: eGFR>30 and 24h U Oxalate >600 umol/24h
- Adult patient with PH1,2 or 3: eGFR between 15 and 90 and relatively high urine oxalate (likely to give plasma oxalate>10 umol/l but it is not necessary to measure this)
- Adult with enteric hyperoxaluria: eGFR>30 and 24h U Oxalate >550 umol/24h
These are with investigational products from Alnylam, Dicerna, Oxthera and Allena respectively.