Original Article
Results of Long-Term Treatment with Orthophosphate and Pyridoxine in Patients with Primary Hyperoxaluria
N Engl J Med 1994; 331:1553-1558December 8, 1994
- Abstract
Background
The prognosis for patients with primary hyperoxaluria has been ominous, with the expectation of renal failure, poor results with transplantation, and early death.
Methods
We studied the long-term effects of orthophosphate and pyridoxine therapy in 25 patients with primary hyperoxaluria who were treated for an average of 10 years (range, 0.3 to 26). Their mean age at the start of treatment was 12 years (median, 6; range, 0.5 to 32). We also studied the effect of orthophosphate and pyridoxine on urinary supersaturation with calcium oxalate, crystal inhibition using a seeded growth system, and crystal formation using scanning electron microscopy in 12 patients during three-day stays in the clinical research center.
Results
The mean (±SD) glomerular filtration rate at the start of treatment was 91 ±26 ml per minute per 1.73 m2. The median decline in glomerular filtration rates was 1.4 ml per minute per 1.73 m2 of body-surface area per year. The actuarial survival free of end-stage renal disease was 96, 89, 74, and 74 percent at 5, 10, 15, and 20 years, respectively. Treatment with orthophosphate and pyridoxine reduced urinary supersaturation with calcium oxalate from 8.3 ±3.0 to 2.1 ±1.7 kJ per mole at 38 °C (P<0.001), increased the inhibition of calcium oxalate formation from 63 ±11 to 108 ±10 inhibitor units per 24 hours (P<0.001), and improved the crystalluria score from 2.6 ±0.3 to 0.6 ±0.1 (P<0.001).
Conclusions
Treatment of patients with primary hyperoxaluria with orthophosphate and pyridoxine decreases urinary calcium oxalate crystallization and appears to preserve renal function.
Media in This Article
Figure 1
Urinary Oxalate Excretion before and during the First 2 to 14 Months of Treatment with Orthophosphate and Pyridoxine in 21 Patients with Type I (solid circles), Type II (solid squares), or an Undetermined Type (solid triangles) of Primary Hyperoxaluria.Figure 2
Changes in the Glomerular Filtration Rate during Treatment with Orthophosphate and Pyridoxine in 24 Patients with Type I, Type II, or an Undetermined Type of Primary Hyperoxaluria.Article Activity
- Article
Primary hyperoxaluria is an autosomal recessive disorder caused by defects in hepatic enzyme systems important in the metabolism of glyoxylate, a major precursor of oxalate1. In type I primary hyperoxaluria, a deficiency or mistargeting of hepatic alanine-glyoxylate transaminase results in increased production of glycolate and oxalate2-5. In type II primary hyperoxaluria, deficiencies in glyoxylate reductase and glycerate dehydrogenase result in increased production of l-glyceric acid and oxalate6,7. The marked excess of oxalate in both disorders is eliminated primarily by renal excretion, leading to the formation of insoluble calcium oxalate in the urine, crystalluria, stone formation, and the deposition of calcium oxalate in the renal parenchyma. With time, renal function declines, serum oxalate concentrations increase, and calcium oxalate is deposited in multiple organs (oxalosis).
Without treatment, the outlook for patients with primary hyperoxaluria is poor. In a recent review, 50 percent of 330 patients had end-stage renal disease by the age of 15 years and 80 percent by the third decade8. Dialysis does not remove sufficient oxalate to match production in patients with primary hyperoxaluria,9 so oxalate continues to be deposited in tissue. The outcome of renal transplantation has been disappointing; three-year rates of allograft survival of 23 percent for recipients of renal transplants from living related donors and 17 percent for recipients of cadaveric grafts were reported recently10. Liver transplantation can correct the enzyme defect11-13 but requires removal of the patient's healthy liver.
Treatment of hyperoxaluria, if initiated when renal function is satisfactory, could reduce the precipitation of calcium oxalate in the urinary tract and improve the long-term outcome. Therapy with magnesium, citrate, and thiazide diuretics has been advocated, but data on the efficacy of these agents are limited14-16. Oral orthophosphate therapy reduces urinary supersaturation with calcium oxalate and renal deposition of calcium oxalate,17,18 and early reports suggested that it was beneficial in patients with primary hyperoxaluria17,19. Pyridoxine is a cofactor in the alanine-glyoxylate transaminase enzyme pathway and may reduce the production of oxalate by inducing enzyme activity20. As many as 30 percent of patients with type I primary hyperoxaluria have a response to pyridoxine20-23. We report our experience in the treatment of patients with primary hyperoxaluria with orthophosphate and pyridoxine.
Methods
Patients
We reviewed the histories and laboratory data of all 32 patients with primary hyperoxaluria who were seen at the Mayo Clinic from 1948 to 1991. Twenty-seven patients who were seen before the onset of renal failure were eligible for treatment. One patient received orthophosphate alone, and one pyridoxine alone. The 25 patients, from 17 unrelated families, who received both drugs are the subject of this report. We saw all the patients once or twice annually. The patients were instructed to drink a glass of water every hour while awake and to continue their usual diet.
Analytic Methods
Before 1980 urinary oxalate was measured by atomic absorption24 (normal reference range, <40 mg [0.45 mmol] per 24 hours). From 1980 to 1988, it was measured according to the method of Olthuis et al.25 (normal reference range, 20 to 60 mg [0.23 to 0.68 mmol] per 24 hours), and after 1988 according to the method involving immobilized oxalate oxidase26 (normal reference range, 10 to 40 mg [0.11 to 0.46 mmol] per 1.73 m2 of body-surface area per day). Urine samples were collected for 24 hours in bottles containing hydrochloric acid to prevent oxalate crystallization and the conversion of ascorbate to oxalate. All urinary oxalate values are expressed in terms of milligrams per 1.73 m2 per 24 hours to allow comparisons between children and adults27. Urinary glycolate and l-glyceric acid were measured by gas chromatography28. The normal reference ranges for glycolate and l-glyceric acid were 14 to 114 μg per milligram of creatinine (21 to 168 μmol per millimole of creatinine) and 22 to 185 μg per milligram of creatinine (24 to 198 μmol per millimole of creatinine), respectively. The glomerular filtration rate was determined on the basis of 24-hour creatinine clearance, clearance of subcutaneous iothalamate sodium,29 the response to an intravenous infusion of inulin, or the Schwartz formula30,31. Enzyme studies of liver tissue were performed by Dr. Christopher Danpure7,32.
Short-Term Studies
Twelve patients (five with type I primary hyperoxaluria, four with type II primary hyperoxaluria, and three with an undetermined type of hyperoxaluria) consented to participate in additional studies approved by the institutional review board to determine the effects of orthophosphate and pyridoxine on calcium oxalate crystalluria, supersaturation with calcium oxalate, and the inhibition of the formation of calcium oxalate crystals. Five were male; their median age was 14 years (range, 5 to 37). These patients were studied in the clinical research center before and an average of 3 times during treatment (range, 1 to 10). Reference values were obtained in 16 normal subjects (7 women and 9 men; median age, 31 years [range, 17 to 39]), who were unrelated to the patients. The patients and normal subjects consumed their usual diet and fluid volume (determined from a two-week diet log and diet history taken by a research dietitian) for three days, during which time two consecutive 24-hour urine samples were collected. Each urine sample was collected in a beaker kept at 37 °C. Two 2-ml aliquots of the urine were filtered immediately by vacuum through 0.22-micrometer Nucleopore membranes that then were rinsed with distilled water. The volume and pH of each sample were measured. Ten percent of each sample was stored under mineral oil, 10 percent in 6 N hydrochloric acid, and the remainder was pooled at 4 °C until the 24-hour collection was completed. The 24-hour pooled urine samples were analyzed for osmolality; sodium, potassium, creatinine, phosphorus, chloride, uric acid, calcium, magnesium, sulfate,33 oxalate,25 citrate,34 ammonium ion, and carbon dioxide content; and crystalluria35. The pooled samples were also analyzed with a seeded growth system36 to determine whether the formation of calcium oxalate crystals was inhibited36. In this system, one inhibitor unit was defined as the concentration of inhibitor required for a 50 percent reduction in the rate of crystal growth under standard conditions. Ionic strength, free ion activity, and urinary supersaturation with calcium oxalate were estimated with the Equil 2 computer program37. The results from the two 24-hour collections were averaged. For patients who were studied more than once during treatment, the results were averaged.
Statistical Analysis
The results are presented as means ±SD unless otherwise specified. Several variables were highly skewed, in which case median values are given. The paired t-test was used to compare pretreatment and treatment results. Trends over time in the glomerular filtration rate, urinary oxalate excretion, and serum concentrations of creatinine, calcium, and phosphorus were evaluated with linear regression analysis. For each patient, the annual rate of change was estimated from the regression of the value of interest against the length of follow-up in years. The median slope for the group was then calculated, and its significance assessed with the signed-rank test. Results after renal transplantation were not included in the analysis of changes in renal clearance, serum creatinine, and urinary oxalate excretion.
Survival from the time of initial treatment to the development of end-stage renal failure (dialysis or transplantation) was estimated with the Kaplan-Meier method. For one patient who began treatment before coming to the Mayo Clinic, the date of the first visit to the clinic was used as the starting time in the survival analysis.
Results
The characteristics of the 25 patients are shown in Table 1Table 1
Characteristics of 25 Patients with Primary Hyperoxaluria.. Eleven (44 percent) were male. Fourteen patients had symptoms before five years of age, and five before one year of age. In only three patients was the diagnosis made before the onset of symptoms as a result of family screening studies, although two of the patients (0.3 and 4.5 years of age) had multiple stones at that time. Most patients had symptoms or signs of urolithiasis, including hematuria in five, pain in eight, stone passage without pain in three, infection in four, and urethral obstruction and inability to void in two; two infants also had crystals in their diapers. One patient had pyuria and fever with negative urine cultures. Four patients had undergone unilateral nephrectomy for urolithiasis and chronic infection or obstruction before being treated with orthophosphate and pyridoxine.Nine patients had type I primary hyperoxaluria (Table 2Table 2
Selected Characteristics of the Patients According to the Type of Primary Hyperoxaluria.). Liver-enzyme studies confirmed a deficiency of alanine-glyoxylate transaminase in the one patient who underwent liver biopsy. An affected sibling of this patient was also assumed to have type I disease. Five patients had type II primary hyperoxaluria, three of whom were described previously38. Liver-enzyme studies confirmed a deficiency of glycerate dehydrogenase in the one patient who had undergone liver biopsy. The subtype of primary hyperoxaluria was not established in 11 patients.Long-Term Studies
Twenty-five patients were treated with orthophosphate and pyridoxine for a total of 257 treatment-years. The mean duration of follow-up was 10 years (Table 1), and the mean age at last follow-up was 24 years (range, 4 to 54).
The early response to therapy (mean duration of treatment, 6 months; range, 2 to 14) was evaluated in 21 patients. In two patients urinary oxalate excretion decreased to normal or nearly normal values (Figure 1Figure 1
Urinary Oxalate Excretion before and during the First 2 to 14 Months of Treatment with Orthophosphate and Pyridoxine in 21 Patients with Type I (solid circles), Type II (solid squares), or an Undetermined Type (solid triangles) of Primary Hyperoxaluria.). In seven other patients, urinary oxalate declined gradually over a period of several years, and three had values below 60 mg (0.68 mmol) per 1.73 m2 per 24 hours at last determination. Table 1 shows the annual percent decrease in urinary oxalate during treatment. No patient had neuropathy or other signs of pyridoxine toxicity.None of the patients had clinical or biochemical evidence of metabolic bone disease during treatment. In the children, growth was normal; the mean height percentile at last follow-up was 56 ±27 (range, 7 to 97). Three patients had transient diarrhea, one had abdominal cramps, and one had mild transient hyperphosphatemia. Orthophosphate was discontinued during periods of renal failure.
Data on urinary phosphorus were available for 19 patients. The mean value during treatment was 1751 ±356 mg (56 ±11 mmol) per 1.73 m2 per 24 hours, as compared with a mean of 992 ±379 mg (32 ±12 mmol) per 1.73 m2 per 24 hours before treatment. Of 139 24-hour urinary phosphorus determinations during treatment, 127 (91 percent) exceeded the normal range. The mean urine volume during treatment was 2144 ±1163 ml per 24 hours, as compared with 1374 ±1013 ml per 24 hours before treatment. These results suggest that compliance with orthophosphate therapy and requests to maintain a high fluid intake were excellent.
Growth of existing stones or the formation of new stones was determined by serial radiographs with tomography. Stone formation could be evaluated in 23 patients, with a median of seven visits per patient. During treatment, eight had new stones or growth of preexisting stones at fewer than 25 percent of visits, four at 25 to 50 percent of visits, and four at more than 50 percent of visits; seven patients had no stone formation. Nine patients had a decrease in stone mass during follow-up as a result of the passage of stones or a reduction in the size of the stones.
The changes in renal function during treatment are shown in Table 1 and Figure 2Figure 2
Changes in the Glomerular Filtration Rate during Treatment with Orthophosphate and Pyridoxine in 24 Patients with Type I, Type II, or an Undetermined Type of Primary Hyperoxaluria.. The median of the slopes of the glomerular filtration rate in each patient plotted against time was not significantly different from the value reported for normal subjects (-0.4 ml per minute per 1.73 m2 per year, P = 0.14)39. The actuarial rates of survival free of end-stage renal disease are shown in Figure 3Figure 3
Survival Free of End-Stage Renal Disease during Treatment with Orthophosphate and Pyridoxine in 25 Patients with Primary Hyperoxaluria.. Five patients had progression to end-stage renal disease after 7, 8, 11, 14, and 23 years of treatment. One of these patients had acute renal failure on two occasions after nephrolithotomy, and end-stage renal disease developed shortly thereafter. Acute renal failure followed by diffuse oxalosis developed in another patient during chemotherapy for metastatic breast carcinoma. She died shortly thereafter of systemic oxalosis at the age of 36 years. There were no other deaths.Four of the five patients with progression to end-stage renal disease underwent transplantation. One underwent transplantation with a cadaveric kidney, which was unsuccessful, and is currently awaiting combined kidney and liver transplantation. In one the first cadaveric kidney graft was rejected, but a subsequent combined kidney and liver transplantation was successful. Two patients underwent successful renal transplantation and continued therapy with orthophosphate and pyridoxine after transplantation. At the time of the most recent follow-up visits, the successful allografts had functioned for seven (kidney and liver grafts), nine, and two years, respectively.
Short-Term Studies
Table 3Table 3
Urinary Constituents before and during Orthophosphate and Pyridoxine Therapy in 12 Patients with Primary Hyperoxaluria and in 16 Normal Subjects. shows urinary constituents before and during orthophosphate and pyridoxine therapy in 12 patients with primary hyperoxaluria and in 16 normal subjects. Urine volume, ionic strength, and osmolality did not change. Calcium oxalate supersaturation and crystal formation decreased, and there was an increase in the inhibition of calcium oxalate formation (Figure 4Figure 4
Changes in Urinary Supersaturation with Calcium Oxalate at 38 °C, Inhibition of the Formation of Calcium Oxalate Crystals, and Crystalluria Score during Treatment with Orthophosphate and Pyridoxine in 12 Patients with Primary Hyperoxaluria.).Discussion
Heretofore, primary hyperoxaluria has carried an ominous prognosis, with expectations of renal failure during childhood or young adulthood, poor results with transplantation, and early death. By contrast, among our patients the actuarial rate of end-stage renal disease was only 26 percent after 20 years of treatment with orthophosphate and pyridoxine, and there was only one death.
Orthophosphate and pyridoxine therapy favorably influenced urinary constituents in our patients with primary hyperoxaluria, resulting in reduced calcium oxalate supersaturation, increased inhibition of the formation of calcium oxalate crystals, and a reduction in crystalluria. The decrease in urinary excretion of calcium and magnesium may be due to decreased intestinal absorption of these cations, although this was not measured. The increased inhibition of crystal growth may have been due to the increase in pyrophosphate and citrate excretion and the increase in pH. Both pyrophosphate and citrate are better inhibitors of crystallization at higher pH values. However, their excretion was not decreased before treatment, despite the deficiency of inhibitors of calcium oxalate-crystal formation in the patients with primary hyperoxaluria present at that time. To the extent that calcium oxalate crystallization can be controlled, progressive renal damage from multiple episodes of urolithiasis, stone-related infection, and oxalate deposition in the renal parenchyma might be prevented. Indeed, renal function was preserved in our patients, including the four patients with solitary kidneys, during many years of follow-up.
Treatment with orthophosphate and pyridoxine was well tolerated. The importance of increasing the dose of orthophosphate during childhood and adolescence was illustrated by the development of new stones or an increase in the size of existing stones during growth spurts in five patients. When the dose was increased, stone formation ceased.
There may be alternative explanations for the improved outcomes among our patients. The diagnosis of primary hyperoxaluria was made early, before substantial renal damage had occurred. The patients maintained a high oral fluid intake and were seen regularly, providing an opportunity for the early detection of problems related to stones and infection. However, in other recent series,8,40-42 the outcome was often poor. Patients who have primary hyperoxaluria before renal failure ensues could have a milder form of the disease. However, the early onset of symptoms in many of our patients, the occurrence of renal failure in three and death in two untreated siblings of our patients at young ages, and information from other series do not support this conclusion.
Clinical heterogeneity was evident among our patients and has been noted by others42-44. The severity of clinical manifestations does not correlate either with urinary oxalate excretion or, in patients with type I primary hyperoxaluria, with hepatic enzyme profiles45,46. Patients whose symptoms begin in infancy or early childhood generally have more severe disease than those with a later onset of symptoms. Yet, among our patients with symptoms before the age of five years who were treated from early childhood with orthophosphate and pyridoxine, the changes in renal function were similar to those in patients whose symptoms began later. Four of the five patients who had symptoms at less than 1 year of age had normal renal function at the most recent follow-up at the ages of 5, 6, 8, and 10 years.
Most studies have not systematically evaluated patients for subtypes of primary hyperoxaluria. In our study the clinical course of patients with type II primary hyperoxaluria seemed more indolent than that of the other patients, although one of these patients required unilateral nephrectomy for severe stone problems before treatment with orthophosphate and pyridoxine was begun. None of the five patients with type II primary hyperoxaluria had end-stage renal disease during treatment, as compared with three of the nine patients with type I primary hyperoxaluria. Our experience suggests that type II primary hyperoxaluria may be more common than is generally recognized.
Our results suggest that early diagnosis of primary hyperoxaluria is advantageous. Treatment with orthophosphate and pyridoxine before the onset of renal failure reduces calcium oxalate crystallization in the urine and appears to preserve renal function.
Supported in part by grants (AM20605 and 5M01-RR00585-23) from the National Institutes of Health.
We are indebted to Mr. Robert Liedtke, Mr. Jan Bergert, and Mr. Robert Rundquist for technical assistance, to Mrs. Tami Fencl and Ms. Monica Poncelet for secretarial help, and to Dr. Christopher Danpure for the hepatic enzyme analyses.
Source Information
From the Division of Nephrology, Departments of Internal Medicine (D.S.M., D.M.W., L.H.S.) and Pediatrics (D.S.M.), and the Section of Biostatistics (J.T.E., E.J.B.), Mayo Clinic, Rochester, Minn.
Address reprint requests to Dr. Milliner at the Division of Nephrology, Mayo Clinic, Rochester, MN 55905.
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