Stones are caused by a deficiency of the liver enzyme alanine-glyoxylate aminotransferase (AGXT), which ordinarily converts glyoxylate to glycine.2,4 When AGXT is absent, glyoxylate is converted instead to oxalate, which forms insoluble salts that accumulate in the kidney as oxalate kidney stones. Most patients (ie, 80% to 90%) present in late childhood or early adolescence with systems of recurrent stones and urinary tract infections resulting from blockage.5,6 The natural history of the disease is progression to kidney failure and death from end-stage renal disease unless dialysis is initiated.
While testing of oxalate-to-creatinine molar ratio in a random urine sample may be helpful, this measurement does not stabilize until age 14 to 18—often after kidney damage has already occurred.7 Liver biopsy can confirm whether the enzyme AGXT is absent. Differentiation between PHO and type 2 hyperoxaluria can only be confirmed by genetic testing in which the AGXT gene is identified.8
There is an increased incidence of PHO in Tunisia and Kuwait9-11 and in the Arab and Druze families of Israel12 as a result of intermarriages in this population. Since AGXT is a recessive gene, the child of parents who are both carriers has a 25% chance of having the disease. If either parent carries the genetic variant, there is a 50% chance that the recessive gene will be passed on.
Diagnosis
Early diagnosis of PHO is critical. However, because the disease is so rare, more than 40% of affected patients do not receive a diagnosis until three years after symptoms develop, and 30% are diagnosed only upon presentation with end-stage renal disease.2,13
If PHO is detected early, the key management goal is to minimize renal and skeletal oxalate deposition. Components of medical management are shown in the table.2,14-17 It is important to note that these strategies are effective only if initiated early, that is, before the patient’s glomerular filtration rate drops below 25 mL/min.18
Treatment
Organ transplantation remains the only definitive treatment for PHO14,19—to prevent severe systemic oxalosis or to manage the patient who has progressed to end-stage renal disease. Researchers from the Mayo Clinic in Rochester, Minnesota (where, it should be noted, a National Oxalosis and Hyperoxaluria Registry is maintained under the direction of Dawn S. Milliner, MD), recently published an observational study of outcomes in transplant graft survival among 203 PHO patients. Bergstralh et al20 reported high rates of recurrent oxalosis in patients undergoing kidney transplantation alone, and significantly improved outcomes in patients who underwent both liver and kidney transplantation.
Before 1990, according to a report by the Rare Kidney Stone Consortium,18 the prognosis for PHO transplant patients in the United States was so poor that a donor kidney was considered wasted on these patients. Since the year 2000, however, survival after transplantation has improved greatly, with rates similar to those of all kidney transplant patients nationwide. The explanation for increased survival rates among PHO patients undergoing transplantation was twofold:
• Increased preoperative stone control
• Use of combined liver-kidney transplants.21,22
Since the liver is responsible for the cascade of calcium oxalate stones, the native liver must be fully removed prior to transplantation of a new liver and kidney. Postoperatively, stones will also emerge from where they have lodged in the skeletal tissue to shower the new kidney. Thus, medical management of this cascade of new stones is vital if the transplanted grafts are to survive.23 Calcium oxalate blood levels can remain high for one to two years posttransplantation,2,24 so long-term medical management of oxalate is essential.
The Case Patient
Clinicians engaged in a discussion with the patient and her family regarding a possible diagnosis of PHO. Blood was drawn and sent to the Mayo Clinic for genetic analysis. It was found that the patient had an abnormality in the AGXT gene; with the diagnosis of type 1 hyperoxaluria confirmed, she was flown to Rochester for a full workup.
The patient was the only member of her family with the defective AGXT gene, and her genetic counselors considered this a single mutation. She was accepted for the liver/kidney transplantation list.
Due to the increase in reported survival among patients if they undergo transplantation early in the natural history of stone deposition, the average wait time for PHO patients is only three to four months. The case patient returned to the dialysis unit in Virginia, where she was placed on a dialysis regimen of five-hour treatments, five times per week (nighttime and day); this was determined to be the peak treatment duration for most efficient stone removal, as determined by calcium oxalate measurement during her workup at the Mayo Clinic.