Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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Chapter 7 / Management of Oxaluria 103

103

From: Current Clinical Urology, Urinary Stone Disease:

A Practical Guide to Medical and Surgical Management

Edited by: M. L. Stoller and M. V. Meng © Humana Press Inc., Totowa, NJ

Management of Patients

With Hyperoxaluria

Ojas Shah, MD, Ross P. Holmes, PhD,

and Dean G. Assimos,

CONTENTS

INTRODUCTION

OXALATE PHYSIOLOGY

SOURCES OF URINARY OXALATE

HYPEROXALURIA: DEFINITION

ENTERIC HYPEROXALURIA

PRIMARY HYPEROXALURIA

POTENTIAL FUTURE THERAPY

CONCLUSIONS

REFERENCES

Key Words: Nephrolithiasis; oxalate; absorption.

INTRODUCTION

Oxalate excretion is a prerequisite for the formation of calcium oxalate stones and the

development of hyperoxaluric states. In this chapter, we review the aspects of oxalate

physiology germane to these conditions, the clinical manifestations of these entities, as

well as therapy.

OXALATE PHYSIOLOGY

Oxalate is a simple dicarboxylic acid and is a major component of the most common

type of renal calculus. The oxalate concentration in urine affects its supersaturation with

calcium oxalate and an increase will promote crystal formation, a key event in cal-

culogenesis. The oxalate in urine is derived from two sources: the diet and endogenous

synthesis. Oxalate is a common component of plants and an unavoidable constituent of

104 Shah, Holmes, and Assimos

human diets. It is a metabolic end product in humans that is linked to a variety of vital

pathways, including gluconeogenesis, glycolysis, ureagenesis, pentose–phosphate path-

way, glyoxylate pathway, serine pathway, and xylulose pathway (1).

Oxalate is freely filtered through the glomerulus and secretory fluxes may also occur

(2–5). Oxalate transport in proximal tubular cells may be complex because it seem to

plays a role as a recycling substrate that functionally links the transcellular absorption

of chloride to that of other anions such as bicarbonate and sulfate (6,7). At the basolateral

membrane, oxalate enters the cell in exchange for sulfate or bicarbonate (6–8). At the

luminal brush border membrane, oxalate can be transported out of the cell in exchange

for chloride and may be transported back into the cell in exchange for sulfate (6, 7).

There is also evidence that oxalate exchange may occur in the distal tubule (9). Various

anion exchange proteins mediate these processes (10,11).

Oxalate is absorbed all along the gastrointestinal tract, including the stomach (12).

Absorptive and secretory pathways for oxalic acid regulated by substances that direct the

net oxalate ion flux have been identified in the proximal and distal segments of rat colon

(13–16). Cations such as calcium and magnesium complex with oxalate in the alimen-

tary tract and limit its absorption. The free anionic form of oxalate is thought to be the

one that is absorbed. Recent oxalate loading studies in healthy volunteers have demon-

strated that oxalate absorption varies tremendously, with 2–18% of a dietary oxalate load

in normal individuals being absorbed (17). In addition, the time sequences of absorption

studies suggest that a significant amount of oxalate is absorbed in the small intestine in

humans. Oxalate is also degraded in the colon by oxalate-degrading bacteria such as

Oxalobacter formigenes and other organisms (18). The actual role that this bacterium

plays in altering intestinal oxalate content and oxalate absorption has not been well

characterized.

A role for the intestinal absorption of dietary oxalate in stone formation was suggested

by the studies of Curhan and associates (19,20). A low-calcium intake was shown to be

a significant risk factor for stone development. The explanation for this finding is that

calcium complexes with oxalate in the alimentary tract thus limiting oxalate absorption.

Metabolic studies in humans support this theory. We demonstrated a 34% increase in

urinary oxalate excretion in normal adult subjects when dietary calcium is reduced from

1002 mg to 391 mg/d while other dietary constituents are unchanged, which is consistent

with this theory (21). In addition, Liebman and Chai found that supplemental calcium

decreased the absorption of an oxalate load in humans by more than 50% (22).

Studies have shown that supraphysiologic concentrations of oxalate can damage

cultured renal tubular cells through free-radical-induced oxidative stress (23–27). Expo-

sure of a line of human renal epithelial cells, HK-2, to oxalate resulted in a programmed

sequence of events that led to an increase in membrane permeability, alterations in cell

morphology and viability, and the re-initiation of DNA synthesis (23). It has been

hypothesized that this concentration-dependent damage promotes a release of lipid-

rich cellular membranes that act as a nidus for crystal nucleation and retention, which

likely leads to lithogenesis (28–31). Although there is currently no evidence that such

events occur in human stone formers, stones do contain lipids in their matrix (32).

The roles of oxalate and calcium in the lithogenic process have nearly always been

attributed to their impact on the supersaturation of urine with calcium oxalate. Some

studies have demonstrated that supersaturation of calcium oxalate in stone formers does

not differ significantly from that in nonstone formers (33,34). However, Borghi et al.

have shown that oxalate-loading in calcium oxalate stone formers was associated with

Chapter 7 / Management of Oxaluria 105

an increased potential for crystal nucleation as compared to controls (35). Supersatura-

tion and nucleation of calcium oxalate are insufficient to explain the formation of stones

alone, but an increased tendency to nucleation may precipitate subsequent events that are

responsible for the formation of stones (36). Additionally, the upper limit of metastabil-

ity in urine samples and the ability of urine components to inhibit crystal growth may be

more sensitive indices in providing discrimination between the urine of stone formers

and normal individuals (34).

SOURCES OF URINARY OXALATE

It was previously thought that the contributions of urinary oxalate were 40–50%

hepatic synthesis, 40–50% breakdown of ascorbic acid (vitamin C), and the remaining

10–20% dietary (37). However, we and others have shown that dietary oxalate is a major

contributor to urinary oxalate excretion in most humans and may account for 50% or

more of the daily urinary oxalate excreted. We have demonstrated that when normal

adults are placed on an oxalate-free formula diet, oxalate excretion decreases about 50%

from the levels on self-selected diets, indicating that dietary oxalate is a major contribu-

tor of urinary oxalate in most individuals (21,22). Dietary oxalate originates almost

exclusively from plant-derived foods (Table 1).

Table 1

Oxalate Content of Various Foods

Oxalate, Oxalate per serving,

mg/100 g mg (serving size, g)

Spinach 645.0 645.0 (100)

Fibre One cereal 142.0 43.0 (30)

Bran flakes 141.0 42.0 (30)

Green beans (steamed) 33.0 33.0 (100)

Potato (raw) 27.1 27.1 (100)

Snack bar (Butterfinger) 53.5 24.0 (45)

Peanut butter 95.8 19.2 (20)

Tea (brewed) 7.5 18.8 (250)

Celery 61.2 18.4 (30)

Chocolate (American) 42.5 13.0 (30)

Ravioli 6.5 13.0 (200)

White bread 14.3 8.0 (56)

Carrots (raw) 5.7 5.7 (100)

Potato chips 9.4 3.0 (30)

White rice (steamed) 2.1 2.1 (100)

Broccoli (steamed) 1.8 1.8 (100)

Strawberry jelly 5.3 1.1 (20)

Corn flakes 1.9 0.6 (30)

Mustard 12.1 0.6 (5)

Apple (raw) 0.5 0.5 (100)

Peaches (canned) 0.3 0.3 (100)

Grape jelly 1.5 0.3 (20)

106 Shah, Holmes, and Assimos

Endogenous oxalate synthesis occurs in the liver. A variety of precursor molecules,

including serine, glycine, hydroxyproline, ethylene glycol, and several carbohydrates,

can lead to production of oxalate via pathways that converge on glycolate and glyoxylate

(38). The key steps are depicted in Fig. 1. This includes the oxidation of glycolate to

glyoxylate catalyzed by glycolate oxidase and oxidation of glyoxylate to oxalate pri-

marily by lactate dehydrogenase. Alanine glyoxylate aminotransferase (AGT), a very

important enzyme located in the hepatic peroxisomal compartment in normal humans,

diverts glyoxylate from oxalate synthesis by a transamination process, with alanine

converted to pyruvate as glyoxylate is converted to glycine (1).

There is still an ongoing debate on whether ascorbic acid metabolism contributes

significantly to the urinary oxalate pool. Ascorbic acid is converted into oxalate by a

process in the liver involving diketogluconic acid as an intermediate, with two carbons

of ascorbic acid being converted into oxalate (39). This conversion of diketogluconate

to oxalate is nonenzymatic, although the extent to which it occurs is controversial. Little

is known about the factors controlling this metabolism. The intake of high doses of

ascorbic acid has been demonstrated to increase urinary oxalate excretion in normal

adult individuals and stone-formers (41).

Fig. 1. Pathways associated with oxalate synthesis in hepatocytes. Transport processes are

shown as the thin, dark arrows and enzymatic reactions as the thicker, lighter arrows. AGT,

alanine:glyoxylate aminotransferase; DAO,

-amino acid oxidase; GCS, glycine cleavage sys-

tem; GO, glycolate oxidase; GOA, glutamate oxaloacetate aminotransferase; GR, glycolate

reductase; HKGA, 4-hydroxy-2-ketoglutarate lyase; HPO, hydroxyproline oxidase; LDH, lac-

tate dehydrogenase; PCD, pyrroline-3-hydroxy-5-carboxylate dehydrogenase; SHMT, serine

hydroxymethyltransferase.

Chapter 7 / Management of Oxaluria 107

HYPEROXALURIA: DEFINITION

The definition of hyperoxaluria has varied in reports in the literature. We analyzed

urinary oxalate excretion in 100 normal adults and 100 adult stone-formers on self-

selected diets. We found a fairly distinct difference at 30 mg of oxalate/g of excreted

creatinine (42). We therefore define hyperoxaluria as anything greater than this level.

The use of creatinine in this ratio limits inaccuracy caused by collection error and

corrects for differences in body size. Other investigators have used different criteria for

defining hyperoxaluria; e.g., greater than 43 mg/d in men and 32 mg/d in women (43).

There are also varied reports of the prevalence of this metabolic disorder in stone form-

ers, with estimates ranging from approx 8–30% (42,44).

There are three types of hyperoxaluria: enteric, primary, and idiopathic. We will

discuss the etiology, manifestation, and treatment options for each.

ENTERIC HYPEROXALURIA

Enteric hyperoxaluria is caused by a variety of functional and anatomic small bowel

problems (Table 2) (37,45–50). It is encountered in approx 5% of patients evaluated in

specialized metabolic stone clinics and should be suspected in any patient with

hyperoxaluria and small bowel abnormality (1). These patients typically also have low

urine volume and diminished calcium, magnesium, and citrate excretion.

Various theories about the mechanism of enteric hyperoxaluria have been postulated.

Oxalate normally complexes with calcium to form an insoluble salt or crystal that is

excreted in feces. The saponification of calcium and magnesium with excess intralumi-

nal fatty acids, secondary to their malabsorption, leaves more free oxalate to be absorbed

by the intestine. Gregory et al. demonstrated increased oxalate absorption in a group of

patients who underwent small bowel bypass surgery for treatment of morbid obesity

(46). These patients absorbed an average of 38% of an oxalate load, compared with 6%

in normal controls. In addition, there is an increased delivery of bile acids and salts to

the colon, which has been demonstrated to increase oxalate uptake in this bowel segment

Table 2

Diseases Associated With Enteric Hyperoxaluria

Diseases involving bowel mucosa

• Crohn’s disease

• Ulcerative colitis

• Celiac sprue

Surgical interruption

• Jejunoileal bypass

• Ileal resection

Other causes of malabsorption and steatorrhea

• Pancreatic insufficiency or resection

• Biliary obstruction or diversion

• Primary biliary cirrhosis

• External biliary drainage

• Bacterial overgrowth

• Blind loop syndrome

108 Shah, Holmes, and Assimos

in animal models (51). The mechanism of this phenomenon has not been identified.

Patients subjected to contemporary bariatric surgery may also develop this problem.

Treatment

If correction or treatment of the underlying bowel pathology is possible, this should

be the initial approach for treatment of patients with enteric hyperoxaluria (Table 3).

These individuals should be encouraged to increase their fluid intake because they are

frequently dehydrated. They should also limit consumption of fat and high oxalate

containing foods.

The administration of calcium salts with meals is recommended for most patients. The

supplemental calcium promotes enteric complexation with oxalate thus limiting oxalate

absorption. Calcium citrate (Citracal, 250 mg), at an initial dose of one to two tablets

three times a day with meals, is the preferred agent as it will also help correct hypo-

citraturia (45,46,52,53). The dose may need to be escalated based on follow-up 24-h

urine assessments.

Table 3

Treating Hyperoxaluria With Medical Therapies

Enteric

• Fluid therapy:

50 mL/kg body weight every 24 h in adults; higher relative intake in children

• Low-fat, low-oxalate diet

• Calcium citrate supplementation

• Magnesium oxide or magnesium gluconate can be substituted or added

• Cholestyramine therapy

• Potassium citrate to correct associated hypocitraturia

• Correct underlying bowel pathology when possible

Primary

• Type 1:

— Fluid therapy (as described above for enteric hyperoxaluria)

— Pyridoxine therapy

— Orthophosphate therapy (not in patients with renal insufficiency)

— Magnesium oxide therapy (select cases)

— Potassium citrate therapy (select cases)

— Sodium citrate therapy (select cases)

— In patients with progressive renal damage leading to failure, combined renal

and liver transplantation

• Type 2:

— Medical therapy similar to type I

— Role of transplantation not well defined

Idiopathic

• Fluid therapy (as described above for enteric hyperoxaluria)

• Low-oxalate diet

• Adequate calcium consumption

• Pyridoxine therapy for patients who do not respond to diet restrictions

Chapter 7 / Management of Oxaluria 109

Magnesium oxide or magnesium gluconate may be substituted or added to this regi-

men. This should be considered in patients who have high normal or increased urinary

calcium excretion and in those with concomitant hypomagnesemia (54–56).

Cholestyramine therapy can be used when there is bile acid malabsorption to bind

fatty acids, bile acids, and oxalate (57,58). Other citrate salts, preferably potassium

citrate, can also be given to correct associated hypocitraturia (59,60). The liquid form

of potassium citrate is preferred as these patients typically have rapid gastrointestinal

transit.

Specific therapies of steatorrhea in certain conditions can be used: gluten-free diet

in celiac sprue, pancreatic enzyme replacement in pancreatic insufficiency, and antibi-

otics in bacterial overgrowth.

PRIMARY HYPEROXALURIA

The primary hyperoxalurias result from endogenous overproduction of oxalate. There

are two main types of primary hyperoxaluria, type I (PH1) and II (PH2). Both are rare

autosomal recessive disorders caused by defects in hepatic enzyme systems important

in the metabolism of glyoxylate. The marked oxalate production in both disorders may

result in calcium oxalate stone formation, nephrocalcinosis, systemic oxalosis, and, in

some, end-stage renal disease.

Primary Hyperoxaluria 1

PH1 is caused by a defect in glyoxylate metabolism attributable to low or absent

activity of the liver-specific peroxisomal enzyme AGT (61). Except for the AGT defect,

peroxisomes in PH1 are normal in almost every respect (62). The functional deficiency

of AGT in PH1 results in a failure to detoxify glyoxylate within the peroxisomes (Fig. 1).

Instead of being transaminated to glycine, glyoxylate is oxidized to oxalate and reduced

to glycolate (10,61,62). As a result, urinary excretion of glycolate and oxalate is signifi-

cantly increased.

The gene encoding for AGT is located on chromosome 2q37.3 (10,63,64). Several

mutations and polymorphisms have been identified thus far and there is considerable

molecular heterogeneity among patients. Half of the patients exhibit no detectable AGT

activity, whereas the other half exhibits residual (2–48%) AGT activity (10,62). How-

ever, even patients with residual activity can become ill and do not differ clinically from

patients without AGT activity. Danpure et al. demonstrated that this occurs because

AGT is mistargeted from the peroxisomes to the mitochondria (10,62,64). Such patients

exhibit residual enzymatic activity, with only 10% or less of the AGT localized in

peroxisomes. This mistargeting defect is observed in approx 30% of all patients with

PH1 (10,65). A number of mechanisms have been suggested to explain the lack of

catalytic activity in those with immunochemically detectable AGT. These include: (1)

presence of a common P11L polymorphism, which decreases the specific activity of

AGT; (2) the presence of the P11FL polymorphism in conjunction with the PH1 specific

mutation, which leads to AGT protein destabilization and aggregation into inclusion

bodies; (3) naturally occurring amino acid substitutions that lead to peroxisome-to-

mitochondrion AGT mistargeting; and (4) interference with cofactor binding (66). These

may be caused by synergism between certain disease-associated mutations and the

common nondisease causing AGT polymorphism, P11L.

110 Shah, Holmes, and Assimos

PH1 typically manifests in patients early in life and should be suspected when oxalate

excretion is greater than 1–2 mmol/1.73 m

/24 h (normal reference range 0.11–0.46

mmol/24 h/1.73 m

) and elevated glycolate excretion (normal range 21–168 µmol per

mmol of creatinine) (1,10,65,67). Glycolate levels are elevated in approximately two-

thirds of patients with PH1. Therefore findings of normal values do not exclude this

diagnosis (10,65). Liver biopsy can be performed to establish a definitive diagnosis. The

AGT activity and immunoreactivity in hepatic tissue are measured (10,65). A search for

disease associated AGT mutations can also be undertaken. The latter approach can be

used for prenatal diagnosis using chorionic villous sampling (68). The diagnosis can now

be established in some patients with polymerase chain testing of blood to screen for

certain AGT gene mutations associated with PH1.

Recurrent urolithiasis and nephrocalcinosis are the main manifestations, and the

combination of the two conditions is characteristic for PH1 and may lead to progres-

sive loss of renal function. Half of the patients with PH1 exhibit their first symptoms

by age 5 (71,72). Approximately 40% of PH1 patients will eventually develop end-

stage renal disease (ESRD) (1). The calculi of PH1 patients almost exclusively consist

of calcium oxalate monohydrate (whewellite) (69,70).

Systemic oxalosis occurs when the critical saturation point for plasma oxalate (levels

>30 µmol/L) is reached, typically early in renal insufficiency (73). Deposition occurs in

every organ and tissue except the liver and can lead to significant morbidity. The skel-

eton is the most crippling site of calcium oxalate deposition. The lesions are character-

istic both in X-rays (radiodense metaphyseal bands, a “bone-within-bone” appearance,

and diffuse demineralization with a coarse trabecular pattern) and in histologic assess-

ments (intraosseous tophi of calcium oxalate and granulomas replacing bone marrow)

(74). Clinical manifestations of oxalate osteopathy are pain, spontaneous fractures, and

erythropoietin-resistant anemia (74,75). Additional sites of oxalate deposits are the

retina, media of the arteries (with subsequent ischemia and gangrene), peripheral ner-

vous system (neuropathy), the heart, thyroid gland, and skin (livedo reticularis) (76).

REATMENT

The goals of therapy are to decrease oxalate production and increase the urinary

solubility of calcium oxalate. Without treatment, the outlook for patients with PH1 is

extremely poor. Latta and Brodehl reviewed 330 patients with PH1 and found that 50%

of 330 patients had ESRD by the age of 15 yr and 80% by the third decade (77). Dialysis

does not remove sufficient oxalate to match its production in these patients (78–80). If

initiated when renal function is satisfactory, treatment of PH1 may improve the long-

term outcome of these patients (67).

Fluid therapy is a key factor in the management of patients with PH1. It has been

recommended that adults with PH1 consume greater than 50 mL/kg body weight every

24 h; a higher relative intake is recommended for pediatric patients (67). It is extremely

important for close follow-up monitoring and to maintain preventative measures to

avoid episodes of dehydration.

Pyridoxine is an essential cofactor in the AGT enzyme pathway and approx 30% of

PH1 patients respond to pyridoxine therapy (81). Pharmacologic doses of pyridoxine

(dose ranges from 2.5 to 20 mg/kg/d) are able to significantly reduce (by at least 30%)

oxalate excretion in one-third of patients (67,83–87). To follow pyridoxine responsive-

ness, reliable baseline urinary oxalate values are needed. A trial of pyridoxine therapy

for at least 3 mo is warranted, although the effects usually occur in 1–2 wk in most cases

Chapter 7 / Management of Oxaluria 111

(76). Very high doses of pyridoxine should be avoided as this may cause peripheral

neuropathy (76). The mechanism of pyridoxine’s action has not been defined. Pyridox-

ine responsiveness is associated with the G17OR and F1521 mutations, the latter causing

mistargeting of AGT.

Orthophosphate therapy has been used in combination with pyridoxine to reduce

stone formation and attenuate calcium oxalate deposition in patients with PH1 (67). Its

mechanism of action is thought to be caused by a resultant increase in pyrophosphate

concentration, a known inhibitor of calcium oxalate crystallization, and perhaps to

decreased calcium excretion (1). A clinical trial of this combination in 25 patients lead

to a significant decrease in stone events and prevented renal deterioration in most

patients at a mean follow-up of 10.3 yr (67). Orthophosphate should not be used in

patients with renal insufficiency.

Magnesium oxide, sodium citrate, and potassium citrate therapy have also been used

in PH1, but the true efficacy of these agents has not been determined. Citrate not only

binds calcium but also is an inhibitor of calcium oxalate crystal nucleation and growth

(88). Although there is clinical and experimental evidence of the beneficial effects of this

therapy, it has been difficult to conclusively prove (89,90). Magnesium is another po-

tential inhibitor of calcium oxalate crystallization because it binds to oxalate.

Patients with PH1 who develop renal failure are best managed by combined liver and

renal transplantation. Renal transplantation alone does not correct the basic hepatic

enzyme abnormality and therefore recurrent disease is a potential problem. Broyer et

al. reviewed the European experience where primarily cadaveric renal transplantation

was performed. The 3-yr graft and patient survivals were 20% and 74%, respectively

(91). Saborio and Scheinman reported on the experience in the United States where

living-related renal transplantation was primarily undertaken. The 6-yr actuarial graft

and patient survivals were 51% and 84%, respectively. However the 10-yr graft sur-

vival rate was only 35% (92).

Because the metabolic defect is in the liver, total hepatectomy is required before liver

and renal transplantation. The first successful, combined liver and kidney transplant for

a patient with PH1 was performed in 1984 (93). The actuarial 5-yr graft and patient

survival rates for this approach in some series have been approx 70% and 80%, respec-

tively. However, recent studies demonstrated that patient survival is better after renal

transplantation. Poor prognostic factors for graft and patient survival include presence

of systemic oxalosis, young age (<5 yr), and history of >2 yr of dialysis. In addition, the

renal function of survivors remains stable over time, between 40 and 60 mL/min/1.73 m

after 5–10 yr (87, 94–96).

Some investigators have performed pre-emptive hepatic transplantation in those

afflicted with PH1. However this approach is controversial. If liver transplantation was

a simple procedure with minimal risks and there were no shortage of organs, preemptive

transplantation would probably be an acceptable treatment option in patients with PH1.

However, there are ethical issues including the risk of graft loss and complications

related to the transplant in a patient who might have done well for several years longer

without such an aggressive intervention. There is also concern about the potential long-

term effects of immunosuppressive drugs including renal toxicity and malignancy.

Isolated liver transplantation can only be successful if renal function is adequate (glom-

erular filtration rate greater than the 40–50 mL/min) (76). If the glomerular filtration

rate is <40 mL/min/1.73 m

, there is a significant risk of eventual renal failure (97).

Results of preemptive liver transplantation have thus far been reasonable (97).

112 Shah, Holmes, and Assimos

Other approaches have been considered for patients with PH1. We evaluated the

short-term efficacy of (

L)-2-oxothiaolidine-4-carboxylate (OTZ) therapy. OTZ is a cys-

teine precursor that is converted to cysteine within the cell and forms a stable adduct

with the aldehyde group of glyoxylate, which could potentially decrease oxalate synthe-

sis. Administration of OTZ has been demonstrated to reduce oxalate excretion in rats

and normal human subjects (98,99). However, it did not result in a reduction in two

patients with PH1 perhaps caused by the extremely large glyoxylate pool. The utiliza-

tion of agents that inhibit glycolate oxidase, a key enzyme in oxalate synthesis, has been

proposed as another therapeutic approach.

The identification and characterization of the AGT gene has stimulated interest in

gene therapy for those afflicted with PH1 (63). Intraportal infusion of recombinant

viruses or macromolecular DNA as gene vectors has been suggested (1). The other

approach involves the surgical removal or ablation of hepatic tissue, isolation of hepa-

tocytes or stem cells, ex vivo transfection of these cells, and infusion of the transfected

hepatocytes into the portal vein (100–102). A major hurdle to overcome is the large size

of the hepatic target which makes vector delivery quite difficult. The ability to maintain

the corrective gene will also need to be established. Surgical or pharmacologic strategies

to reduce the targeted hepatic mass will be necessary to facilitate adequate gene delivery;

another impediment.

Primary Hyperoxaluria (PH2)

PH2 results from a deficiency in glyoxylate reductase (GR) activity which leads to

an increased oxalate synthesis and urinary excretion (103–106). The responsible gene,

GRHPR, is mapped to the centromeric region of chromosome 9 (107). Although the

liver has the highest GR activity, the enzyme is ubiquitously expressed in all tissues,

perhaps indicating that all tissues synthesize glyoxylate. As with PH1, a range of

different mutations has been identified, although one mutation predominates in Cau-

casians (108). Clinical manifestations are not as severe as in PH1, although ESRD can

result (109). The metabolic features of PH2 are increased urinary excretion of L-

glycerate and oxalate. The conservative stone prevention treatments used with PH1

patients can also be applied to PH2 patients. However the efficacy of pyridoxine

therapy and liver transplantation has not been established. Owing to the ubiquitous

expression of GR activity, liver transplantation may not be as effective.

Another group of patients with hyperoxaluria in the primary hyperoxaluria range has

been identified which do not have the metabolic characteristics of PH1 and PH2 (110).

The mechanisms of this novel form of hyperoxaluria have not yet been defined.

Idiopathic Hyperoxaluria

Idiopathic hyperoxaluria is the most common type of hyperoxaluria. Patients fre-

quently have other coexistent metabolic abnormalities that should also be addressed.

Dietary modifications should be initially considered for treatment (Table 3). Given

that a significant amount of urinary oxalate is derived from dietary sources, patients

should refrain from consuming high oxalate containing foods (Table 1). Approximately

one-third of patients with idiopathic hyperoxaluria are protein sensitive, with increased

animal protein consumption leading to increased urinary oxalate excretion (111,112).

Therefore, animal protein restriction should be considered for this reason as well as the