The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - Over the past 24 years, the prevalence of indications for pediatric heart transplantation resulting from congenital heart disease has changed. Transplantation for failed SV palliation, including failed Fontan procedure, has now become the predominant indication, according to the observations of a single-center experience reported in the J. Maxwell Chamberlain Memorial Paper for Congenital Heart Surgery at the annual meeting of the Society of Thoracic Surgeons.

Heart transplantation is the only viable treatment for children with end-stage heart failure resulting from either congenital heart disease (CHD) or cardiomyopathy. The purpose of this study by Dr. Rochus K. Voeller and his colleagues at Washington University in St. Louis was to review the trends in the indications for transplant and survival following transplant, using a retrospective review of all 307 orthotopic heart transplants performed at St. Louis Children's Hospital from January 1986 to December 2009. Combined heart-lung transplants were excluded from the study.

The indications for transplantation in 1986-2009 were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 174 patients with CHD, 80% had single-ventricle anomalies (SV). In the CHD group, transplantation for failed SV palliation, including the failed Fontan procedure, became the predominant indication in the latest 8-year interval of their program (increasing from 11% in the 1984-1993 period to 60% in the 2002-2009 period). The rate of retransplantation remained low and unchanged across the various time periods, according to Dr. Voeller.

The mean recipient age was 6.1 years, with 41% of the recipients aged younger than 1 year at the time of transplantation. Nearly one-third of all patients had prior surgical procedures or surgery ranging from banding to Fontan operations; 55% of the patients were boys; 8% of patients were bridged with either ECMO (extracorporeal circulation membrane oxygenation) or VAD (ventricular assist devices).

Overall survival of transplant patients was 81%, 76%, 72%, and 65% at 1, 3, 5, and 10 years, respectively. Survival was best in those patients who were transplanted for cardiomyopathy (1-, 3-, 5-, and 10-year survival of 90%, 84%, 81%, and 81%, respectively) and worst in patients with failed palliations for SV anomalies, especially failed Fontan procedures (1-, 3-, 5-, and 10-year survival of 66%, 61%, 61%, and 53%, respectively).

"Our results demonstrate the high-risk nature of transplants in patients with failed palliations for SV anomalies, including Fontan procedures performed during infancy. As the survival with early palliation for SV anomaly patients improves, more centers will be referred with these patients who will require transplantation at some point," said Dr. Voeller in an interview.

"This will not only impact pediatric heart transplant programs, but it will also influence adult transplant programs as well. Patients following SV palliation, including Fontan procedure, are much more difficult patients to transplant because of a variety of factors. Risk factor analysis will be needed to determine which patients might benefit from earlier transplant referral and how to better prepare these patient for transplant in order to reduce the risk of the procedure," he concluded.

Dr. Voeller reported that none of the authors had any financial disclosures.

SAN DIEGO - Over the past 24 years, the prevalence of indications for pediatric heart transplantation resulting from congenital heart disease has changed. Transplantation for failed SV palliation, including failed Fontan procedure, has now become the predominant indication, according to the observations of a single-center experience reported in the J. Maxwell Chamberlain Memorial Paper for Congenital Heart Surgery at the annual meeting of the Society of Thoracic Surgeons.

Heart transplantation is the only viable treatment for children with end-stage heart failure resulting from either congenital heart disease (CHD) or cardiomyopathy. The purpose of this study by Dr. Rochus K. Voeller and his colleagues at Washington University in St. Louis was to review the trends in the indications for transplant and survival following transplant, using a retrospective review of all 307 orthotopic heart transplants performed at St. Louis Children's Hospital from January 1986 to December 2009. Combined heart-lung transplants were excluded from the study.

The indications for transplantation in 1986-2009 were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 174 patients with CHD, 80% had single-ventricle anomalies (SV). In the CHD group, transplantation for failed SV palliation, including the failed Fontan procedure, became the predominant indication in the latest 8-year interval of their program (increasing from 11% in the 1984-1993 period to 60% in the 2002-2009 period). The rate of retransplantation remained low and unchanged across the various time periods, according to Dr. Voeller.

The mean recipient age was 6.1 years, with 41% of the recipients aged younger than 1 year at the time of transplantation. Nearly one-third of all patients had prior surgical procedures or surgery ranging from banding to Fontan operations; 55% of the patients were boys; 8% of patients were bridged with either ECMO (extracorporeal circulation membrane oxygenation) or VAD (ventricular assist devices).

Overall survival of transplant patients was 81%, 76%, 72%, and 65% at 1, 3, 5, and 10 years, respectively. Survival was best in those patients who were transplanted for cardiomyopathy (1-, 3-, 5-, and 10-year survival of 90%, 84%, 81%, and 81%, respectively) and worst in patients with failed palliations for SV anomalies, especially failed Fontan procedures (1-, 3-, 5-, and 10-year survival of 66%, 61%, 61%, and 53%, respectively).

"Our results demonstrate the high-risk nature of transplants in patients with failed palliations for SV anomalies, including Fontan procedures performed during infancy. As the survival with early palliation for SV anomaly patients improves, more centers will be referred with these patients who will require transplantation at some point," said Dr. Voeller in an interview.

"This will not only impact pediatric heart transplant programs, but it will also influence adult transplant programs as well. Patients following SV palliation, including Fontan procedure, are much more difficult patients to transplant because of a variety of factors. Risk factor analysis will be needed to determine which patients might benefit from earlier transplant referral and how to better prepare these patient for transplant in order to reduce the risk of the procedure," he concluded.

Dr. Voeller reported that none of the authors had any financial disclosures.

SAN DIEGO - Over the past 24 years, the prevalence of indications for pediatric heart transplantation resulting from congenital heart disease has changed. Transplantation for failed SV palliation, including failed Fontan procedure, has now become the predominant indication, according to the observations of a single-center experience reported in the J. Maxwell Chamberlain Memorial Paper for Congenital Heart Surgery at the annual meeting of the Society of Thoracic Surgeons.

Heart transplantation is the only viable treatment for children with end-stage heart failure resulting from either congenital heart disease (CHD) or cardiomyopathy. The purpose of this study by Dr. Rochus K. Voeller and his colleagues at Washington University in St. Louis was to review the trends in the indications for transplant and survival following transplant, using a retrospective review of all 307 orthotopic heart transplants performed at St. Louis Children's Hospital from January 1986 to December 2009. Combined heart-lung transplants were excluded from the study.

The indications for transplantation in 1986-2009 were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 174 patients with CHD, 80% had single-ventricle anomalies (SV). In the CHD group, transplantation for failed SV palliation, including the failed Fontan procedure, became the predominant indication in the latest 8-year interval of their program (increasing from 11% in the 1984-1993 period to 60% in the 2002-2009 period). The rate of retransplantation remained low and unchanged across the various time periods, according to Dr. Voeller.

The mean recipient age was 6.1 years, with 41% of the recipients aged younger than 1 year at the time of transplantation. Nearly one-third of all patients had prior surgical procedures or surgery ranging from banding to Fontan operations; 55% of the patients were boys; 8% of patients were bridged with either ECMO (extracorporeal circulation membrane oxygenation) or VAD (ventricular assist devices).

Overall survival of transplant patients was 81%, 76%, 72%, and 65% at 1, 3, 5, and 10 years, respectively. Survival was best in those patients who were transplanted for cardiomyopathy (1-, 3-, 5-, and 10-year survival of 90%, 84%, 81%, and 81%, respectively) and worst in patients with failed palliations for SV anomalies, especially failed Fontan procedures (1-, 3-, 5-, and 10-year survival of 66%, 61%, 61%, and 53%, respectively).

"Our results demonstrate the high-risk nature of transplants in patients with failed palliations for SV anomalies, including Fontan procedures performed during infancy. As the survival with early palliation for SV anomaly patients improves, more centers will be referred with these patients who will require transplantation at some point," said Dr. Voeller in an interview.

"This will not only impact pediatric heart transplant programs, but it will also influence adult transplant programs as well. Patients following SV palliation, including Fontan procedure, are much more difficult patients to transplant because of a variety of factors. Risk factor analysis will be needed to determine which patients might benefit from earlier transplant referral and how to better prepare these patient for transplant in order to reduce the risk of the procedure," he concluded.

Dr. Voeller reported that none of the authors had any financial disclosures.

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

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
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.