Grand Rounds: Woman, 26, with Kidney Stones

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

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 Kuwait^9-11 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 PHO^14,19—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.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

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 Kuwait^9-11 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 PHO^14,19—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.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

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 Kuwait^9-11 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 PHO^14,19—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.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
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