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DISEASE OF THE MONTH |
*
Division of Pediatric Nephrology, University Children's Hospital, Zurich,
Switzerland
Division of Pediatric Nephrology, University Children's Hospital, Cologne,
Germany.
Correspondence to Dr. Ernst Leumann, Division of Pediatric Nephrology, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland. Phone: +41-1-266-7111; Fax: +41-1-266-7171; E-mail: E.Leumann{at}swissonline.ch
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Introduction |
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 Top Introduction PH1Treatment in ESRFPH2Atypical PHConclusionsReferences |
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PH1 |
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The gene coding for AGT, i.e., AGXT, is located on chromosome 2q37.3 and consists of 11 exons spanning approximately 10 kb (2,5). More than 30 mutations have been identified to date. There is considerable molecular heterogeneity; many patients are compound heterozygotes (frequently with only one allele identified), whereas populations with high rates of consanguinity, e.g., Israeli Arabs (6) or Northwest Africans (7), exhibit mutations in a homozygous pattern. One-half of the patients exhibit no detectable AGT catalytic activity, whereas the other half exhibit residual (2 to 48%) AGT activity (2,4).
Why do individuals with residual AGT activity become ill, not differing
clinically from patients with absent AGT activity? AGT is mistargeted from the
peroxisomes to the mitochondria, as elegantly demonstrated by Danpure and
co-workers
(2,4,5).
Although such patients often exhibit considerable residual enzymatic activity,
only 10% of the immunoreactive AGT (cross-reacting material—positive) is
localized within the peroxisomes; 90% is found within the mitochondria, where
it is metabolically inactive. In his laureate speech,
Günter Blobel, the 1999 recipient of the Nobel
Prize in Medicine, referred specifically to PH1, in which the altered sorting
signal leads to erroneous intracellular localization of the enzyme
(http://www.nobel.se). This protein-trafficking defect is unparalleled in
human subjects (2). It is
observed in approximately 30% of all patients with PH1, usually as the result
of a 630G
A mutation (associated with a Pro11Leu polymorphism), which
leads to a Gly170Arg amino acid substitution, or, less often, as the result of
a 576TA mutation
(2,8).
Pathophysiology
Urine is a saturated solution, and its concentration can change very
drastically within a short time
(9). Stone formation or the
development of nephrocalcinosis thus occurs when the delicate interplay
between promotors (in PH1, especially oxalate) and inhibitors (e.g.,
citrate, magnesium, and glycosaminoglycans) of crystal formation is disturbed
(9,10).
In PH1, the urine is supersaturated with respect to CaOx (urinary CaOx
saturation of >10 relative units)
(2,8,11).
This produces renal calculi, medullary nephrocalcinosis, or both.
Oxalate is freely filtered in the glomerulus and is both secreted and reabsorbed in the proximal tubule (2). Oxalate transport across proximal tubular cells is complex, because this anion plays a role as a recycling substrate that functionally links the transcellular absorption of chloride to that of other anions (bicarbonate and sulfate) (12). At the basolateral membrane, oxalate enters the cell in exchange for sulfate or bicarbonate, via Sat-1 (12). At the luminal brush border membrane, oxalate is transported out of the cell in exchange for chloride and is transported back into the cell in exchange for sulfate. The overall result is a net secretion rate of 10 to 30%, corresponding to fractional oxalate excretion (Cox/Cin) of 1.09 to 1.28 (2).
With physiologic concentrations of oxalate, occasional crystals either are passed as crystalluria particles or are endocytosed by renal epithelial cells (13). Endocytosed crystals are eliminated or are exocytosed to the basolateral side of the cells. From there, the crystals migrate to the interstitium, where they may eventually be destroyed by local inflammatory reactions involving macrophages (14). In PH1, far more oxalate is filtered in the glomeruli than under normal conditions, leading to extremely high oxalate concentrations within the proximal tubular cells. Until recently, these high oxalate concentrations were not considered to be harmful themselves, apart from the risk of CaOx deposit formation in the renal interstitium, followed by foreign-body reactions. However, it is now well established that high oxalate levels have direct toxic effects on renal tubular cells (15). Oxalate reduces both the growth rate and life span of LLC-PK1 cells (which resemble proximal tubular cells), in a concentration-dependent manner (15,16). Whereas oxalate acts as a mitogen at low concentrations, it is a toxic agent at high concentrations (16). These negative effects at the cellular level resemble those observed in other tissues after oxidative stress (15). Indeed, oxalate seems to promote the production of free radicals, which may explain its cellular toxicity (15,17). Because such effects are clearly concentration-dependent, this mechanism may directly contribute to rapid deterioration of renal function in PH1, which is much greater than that observed with nephrocalcinosis of other origins. In addition, the high plasma oxalate levels of patients with PH1 and renal insufficiency may exert toxic effects on other organs and tissues (18).
Both plasma oxalate levels and plasma CaOx saturation values are significantly higher for patients with PH1 than for normal control subjects, even with normal renal function (19,20,21). The two parameters increase concomitantly (19,20,21) and are inversely correlated with the GFR (19). Plasma CaOx supersaturation (plasma CaOx saturation of >1), with plasma oxalate levels of >30 µM, is observed with a GFR of <45 ml/min per 1.73 m2, in contrast to non-PH1 patients, for whom supersaturation occurs only with a GFR of <8 ml/min per 1.73m2 (18,19,21). CaOx crystal deposition therefore begins early in PH1, and patients are at risk of systemic CaOx deposition before the stage of chronic renal failure (19).
Diagnosis
Unfortunately, the diagnosis of PH1 is often overlooked or delayed;
therefore, different diagnostic procedures are briefly discussed here.
Analysis of Urine. Hyperoxaluria is the hallmark of PH1. Urinary oxalate excretion is usually greatly elevated among patients with PH1 and recurrent urolithiasis and/or nephrocalcinosis, exceeding 2 mmol/24 h per 1.73 m2 and sometimes even 4 mmol/24 h per 1.73 m2 (normal, <0.5 mmol/24 h per 1.73 m2 or <45 mg/24 h per 1.73 m2) (2,8). However, family studies have demonstrated that some untreated patients with PH1 may exhibit only slightly elevated (0.5 to 1 mmol/24 h per 1.73 m2) or even normal urinary oxalate excretion (22). Frequent sources of error are (1) incorrect urine collection (acidification to pH <2 is required to prevent deposition of insoluble CaOx), (2) failure to convert 24-h oxalate excretion values for pediatric patients to the adult surface area (1.73 m2) or to consult age-related tables for oxalate/creatinine ratios (8,10), and (3) renal insufficiency associated with oxalate retention and reduced urinary excretion. In such cases, plasma oxalate determinations may be helpful. Glycolate levels are elevated in only approximately two-thirds of patients with PH1; therefore, findings of normal values (which are in the same range as those for oxalate, in milligrams or millimoles) do not exclude this diagnosis (2,8).
Plasma Oxalate Measurement. In patients with PH1, plasma oxalate levels, which are already elevated (>6.3 µM) with normal renal function, are significantly higher (>80 to 100 µM) in ESRF, compared with those for patients without PH1 (40 to 60 µM) (18,19,21).
Liver Biopsy Assessment. A definitive diagnosis (which is essential if liver transplantation is being considered) requires assessments of AGT activity and immunoreactivity in hepatic tissue (minimum of 2 mg), unless the diagnosis has been established at the molecular level (2,8). Testing for both PH1 and PH2 can be performed with the same needle-biopsy specimen of the liver (23).
DNA Analysis. Patients with PH1 are frequently compound heterozygotes, and the mutation on the second allele often remains unidentified, which renders DNA analysis impractical as a diagnostic procedure (2,8). However, selective screening among populations with high incidences of specific homozygous mutations (e.g., Ile244Thr in North African patients) would be feasible (7). Prenatal diagnosis can be performed by linkage analysis using chorionic villous biopsy samples, if the family has been demonstrated to be informative for the linkage marker (24). Genetic counseling must take into account, however, the fact that family members carrying identical mutations may exhibit grossly discordant clinical features (22).
Stone Analysis. The calculi of patients with PH1 consist almost exclusively of pure CaOx monohydrate (whewellite); this finding may yield a diagnostic clue (25,26). Microscopic analysis reveals a characteristic subtype (subtype 1c) that is virtually pathognomonic for PH1 (25).
Bone biopsies for patients with renal failure, to demonstrate birefringent CaOx crystals, were previously used for diagnosis. Eyeground examinations are diagnostically important (Figure 2).
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Clinical Manifestations
Recurrent urolithiasis and nephrocalcinosis are the main symptoms, and the
combination of the two conditions, leading to progressive loss of renal
function, is characteristic for PH1 (Figure
2). One-half of the patients exhibit their first symptoms by the
age of 5 yr (range, 1st month of life to 6th decade)
(27,28).
Diagnosis is usually delayed by 
5 yr, except among infants
(28). Although PH1 is a
monogenic disease, the clinical severity is not correlated with the mutation
or the degree of residual functional AGT activity
(2,4,22).
The clinical, biochemical, and genetic heterogeneity is very large, with some
patients presenting in infancy with renal failure and others experiencing only
occasional passage of stones in adult life, with maintained renal function
(2,4,22,27,28).
Family screening has demonstrated that some patients are completely without
symptoms (with neither nephrocalcinosis nor stones)
(22,28).
Even members of the same family, with identical mutations, may exhibit
completely different clinical phenotypes, e.g., severe infantile
oxalosis, compared with absent clinical findings
(22).
In a malignant variant (infantile PH1), the first symptoms occur very early (median age, 4 mo), and affected infants present at a median age of 6 mo with the triad of a failure to thrive, severe metabolic acidosis, and anemia, all of which are secondary to renal failure (29). This infantile form is characterized by rapid progression to ESRF and severe systemic oxalosis (29). Why these infants rapidly develop diffuse nephrocalcinosis (Figure 2) but not urolithiasis is not clear.
Systemic Oxalosis. Oxalate is systemically deposited when the critical saturation point for plasma oxalate (plasma oxalate levels of >30 µM) is reached, i.e., early in renal insufficiency (19). Deposition occurs in every organ and tissue except the liver and leads to disastrous complications, which should be prevented by all possible means. The bones are the most crippling site of CaOx deposition. The bone oxalate content in ESRF is considerably higher (15 to 910 µmol oxalate/g bony tissue) than that among patients without PH1 (2 to 9 µmol/g) (30). The lesions are characteristic both in x-rays (radiodense metaphyseal bands, a "bone-within-bone" appearance, and diffuse demineralization with a coarse trabecular pattern) and in histologic assessments (intraosseous tophi of CaOx and granulomas replacing bone marrow) (31). Clinical manifestations of oxalate osteopathy are pain, spontaneous fractures, and erythropoietin-resistant anemia (31,32). Retinal CaOx deposits, which are easy to diagnose, may be one of the first obvious signs of systemic oxalosis (Figure 2) (33). Additional important sites of CaOx deposits are the media of the arteries (with subsequent ischemia and gangrene), the peripheral nervous system (neuropathy), the myocardium (atrioventricular block), the thyroid gland, and the skin (livedo reticularis).
Epidemiologic Features and Prognoses
Because the diagnosis is often delayed or overlooked
(27,28,34),
the incidence of PH1 is easily underestimated. Data from the United Kingdom,
Switzerland, and France suggest that 1 in 60,000 to 120,000 children has PH1
(27,28,35).
The disease is far more common in certain countries such as Tunisia, where PH1
is the cause of ESRF for 13% of pediatric patients, compared with <0.7% (of
those treated for ESRF) in North America and Europe
(6,35).
Clinical reports on PH1 are biased; of 330 patients reported, one-half were
experiencing ESRF by the age of 15 yr
(36). This finding contrasts
with data from surveys performed in Switzerland and France, which demonstrated
that ESRF occurred in 20% of patients by the age of 15 yr and in 50% of
patients by the age of 25 yr
(27,28).
However, infantile oxalosis has a particularly poor prognosis, with one-half
of the patients experiencing ESRF at the time of diagnosis and 80% developing
ESRF by the age of 3 yr
(29).
The prediction of outcomes for individual patients is very difficult, if not impossible. Indeed, almost no renal disease is more problematic in this respect. Patients with PH1 with GFR of >50 ml/min may remain in stable condition for many years but may rapidly and irreversibly lose residual function during episodes of dehydration, urinary obstruction, or noncompliance. Nevertheless, the prognoses for patients with PH1 tend to be considerably better, if the disease is properly treated, than suggested in the literature.
Treatment
Conservative Therapy. The aims of therapy are to decrease oxalate
production and to increase the urinary solubility of CaOx. The importance of
close follow-up monitoring and of preventive measures to avoid episodes of
dehydration cannot be overemphasized.
Pyridoxine. Pyridoxal phosphate is an essential cofactor for
aminotransferases such as AGT, and pharmacologic doses of pyridoxine (stepwise
increases from 5 to 20 mg/kg per d, according to urinary oxalate excretion)
are able to significantly reduce (by at least 30%) hyperoxaluria in one-third
of patients (35). The patients
most likely to respond are those with residual AGT activity
(37). For assessment of
pyridoxine responsiveness, reliable baseline values (a minimum of three) for
urinary oxalate excretion are required. A trial of not less than 3 mo is
warranted [determination of plasma oxalate levels is helpful in renal
insufficiency
(19,37)],
although the effects are visible within 1 to 2 wk in most instances. Young
infants may exhibit different behavior. Indeed, a 1-mo-old infant (with a
630GA mutation) who failed to respond to high doses of pyridoxine in 2
mo exhibited a full response, within 1 wk, 14 yr later (E. Leumann,
unpublished observations). Very high doses (>30 mg/kg) are unnecessary and
may lead to peripheral neuropathy. Occasionally, even low doses (20 mg/d) of
pyridoxine may suffice (38).
Pyridoxine responsiveness is still poorly understood at the molecular level
(2). Direct pharmacologic
interventions to reduce the glyoxylate or glycolate pools have not yet been
successful (35).
Enhancement of Solubility. Enhancement of the solubility of CaOx is essential. The most important and straightforward measure is to ensure a constant generous fluid intake (>2.5 L/m2 surface area per day), to avoid urinary oxalate concentrations exceeding 0.5 mM (or at most 0.8 mM); untreated patients with PH1 often exhibit values well above 1 mM. For infants, this may require continuous fluid administration via a nasogastric tube or gastrostomy. In addition, drugs that increase the urinary solubility product are of great importance. Orthophosphate (20 to 60 mg/kg body wt per d) has been demonstrated to reduce stone formation and delay CaOx deposition (39), and the same is true for alkali citrate (11). Citrate not only binds calcium but also is an inhibitor of CaOx crystal nucleation and growth (9). We use potassium citrate or a mixture of potassium citrate and sodium citrate (0.1 to 0.15 g/kg body wt per d), in three or four doses. Although there is experimental and clinical evidence for the beneficial effects of this treatment (11), it is difficult to conclusively prove its efficacy because of the sometimes unpredictable course of PH1. Magnesium is another potential inhibitor of CaOx aggregation, because it binds, instead of calcium, to oxalate. Therefore, a combination of alkali citrate and magnesium might enhance the inhibitory effects.
Diet. Oxalate absorption studies using a stable isotope (13C2) suggested that intestinal absorption is <10% in healthy subjects (40). However, the contribution of dietary oxalate to the oxalate excreted in the urine is close to 50% in healthy individuals and exhibits great variation (10 to 72%) (41). People who lack the intestinal oxalate-degrading bacteria Oxalobacter formigenes exhibit greater dietary oxalate absorption (42). However, for patients with PH, oxalate of dietary origin contributes little to hyperoxaluria, because of their extremely high levels of endogenous oxalate production. It is therefore sufficient to avoid food with very high oxalate contents (beet root, spinach, rhubarb, and ice tea).
Calcium restriction is not recommended, because less intestinal calcium would then be available to bind oxalate and to form insoluble CaOx complexes in the gut. Protein restriction has no place, because glycine, the precursor of glyoxylate (Figure 1), is not an essential amino acid. Vitamin C supplementation is not recommended, although ascorbic acid (a precursor of oxalate) contributes little to hyperoxaluria.
Extracorporeal shock wave lithotripsy should be used with caution and only after generous hydration, because it may seriously harm the kidneys of patients with PH1 and nephrocalcinosis (43).
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Treatment in ESRF |
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Isolated Kidney Transplantation. Except among the few patients who respond well to pyridoxine (37), recurrent nephrocalcinosis and stone formation are expected to occur. Particular risk factors are long ischemia times (cold or warm) and any periods of graft dysfunction. The results of isolated, mostly cadaveric, kidney transplants performed in Europe in the 1980s were very poor, with 3-yr survival rates of only 20% for grafts and 74% for patients (46). This treatment modality has thus been largely abandoned there, in favor of combined liver/kidney transplantation. In contrast, isolated kidney transplantation (preferably with living related donors) is still favored in the United States (47). The medium-term results were acceptable, with actuarial 6-yr survival rates of 84% for patients and 51% for grafts; however, the 10-yr graft survival rate was only 35% (47).
Combined Liver/Kidney Transplantation. The first liver transplant for a patient with PH1 was performed in 1984, before the basic enzymatic defect had been identified (48). Because the metabolic defect is in the liver, it is necessary to perform a total hepatectomy, although the liver is normal in every other respect (2). Auxiliary liver transplantation is not an option, because it would not affect oxalate overproduction by the patient's own liver (2,49). To date, >100 combined liver/kidney transplants have been performed in Europe, according to the European Oxalosis Registry (Cambridge, UK) (50,51). Actuarial 5-yr survival rates (for 98 grafts in 93 patients) were 80% for patients and 71% for liver grafts (35,50,51). Notably, renal function has remained stable, with creatinine clearance rates of 40 to 60 ml/min per 1.73 m2 after 5 yr.
Specific risk factors are young age (<5 yr) and long duration of dialysis (>2 yr) (35,50,51). If the renal graft immediately begins to function, there is no reason to perform additional hemodialysis or hemofiltration. Administration of generous amounts of fluids and treatment with alkali citrate during the first months are essential, because of the slow mobilization of the accumulated body stores of CaOx (18,37). In fact, both plasma oxalate levels and plasma CaOx saturation values, as well as urinary oxalate excretion, remain elevated for several months or even years after successful combined liver/kidney transplantation (2,18,37). In contrast, increased levels among patients without PH are normalized within 3 wk after transplantation (18,52).
Preemptive (Isolated) Liver Transplantation. The rationale for preemptively performing liver transplantation, instead of waiting until ESRF occurs, initially seems straightforward (49). Indeed, if liver transplantation were a relatively harmless procedure and there were no shortage of organs, preemptive transplantation would probably be an accepted treatment method for many patients with PH1. However, the risks of graft loss or even the death of a patient who might have lived several years longer without any intervention raise serious ethical questions. Of additional concern is the need for immunosuppressive therapy with drugs that may severely compromise residual renal function and accelerate the onset of renal insufficiency. To date, more than a dozen patients with PH1 who were not experiencing renal failure have been treated in this way, with reasonable results (49). However, some of the patients might have maintained their renal function without intervention. The major problem concerns the timing of transplantation, because the natural course of the disease is so difficult to predict. Obviously, isolated liver transplantation can be successful only if renal failure is not too far advanced; the minimal GFR is probably 40 ml/min, or even 50 to 70 ml/min, with plasma oxalate levels of <30 µM (8,18). If the GFR is <40 ml/min per 1.73 m2, there is a high risk of rapid further decline, necessitating secondary kidney transplantation (49). Obviously, the overall results of isolated liver transplantation should be better with better residual renal function. However, with better preservation of renal function, the risks and efforts involved become increasingly disproportionate, with respect to the potential benefits of such a procedure.
Treatment in ESRF among Infants and in Developing Countries. Therapy for infants with the malignant variant of PH1 presents particular problems. Because of their small size, such patients require peritoneal dialysis for extended periods, which is invariably leading to progressive systemic oxalosis, until combined liver/kidney transplantation becomes technically feasible. Some developing countries exhibit a high incidence of PH1 but lack the necessary infrastructure and resources for organ transplantation (29). Because dialysis is not a suitable alternative treatment for PH1, except for very limited periods, therapeutic withdrawal in both situations is an option that raises serious ethical questions (29).
Prospects for Gene Therapy. Enzyme replacement therapy via liver transplantation might be considered an extreme form of gene therapy. Considerable problems must be solved before gene therapy in the strictly defined sense becomes applicable. By analogy to auxiliary liver transplantation (which does not work because oxalate is still produced in excess), gene therapy would require transfection of far more than 20 or 30% of liver cells, which is impossible to perform with current vector technology (53). Another potentially beneficial approach involves increasing the level of ATG expression (i.e., AGT activity) per cell by using superactive AGT constructs (C. J. Danpure, personal communication, July 2000); this approach would not yield higher overall transfection efficiency (i.e., the percentage of cells expressing AGT). Whether gene therapy alone, even with such constructs, would be able to compensate for the ongoing abnormal endogenous oxalate production by nontransfected cells is a matter of debate. The question of how often such gene therapy would need to be repeated is also unresolved.
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PH2 |
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TopIntroductionPH1Treatment in ESRFPH2Atypical PHConclusionsReferences |
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PH2 results from the deficiency of a cytosolic enzyme with glyoxylate reductase, hydroxypyruvate reductase, and D-glycerate dehydrogenase activities (Figure 1) (23,55,56). The tissue concentration of glyoxylate reductase/hydroxypyruvate reductase is high in the liver but low in the kidneys, lymphocytes, and fibroblasts (23). Diagnoses of PH2 can be confirmed by measurements of the glyoxylate reductase activity in liver biopsy samples (23). The responsible gene, GRHPR, was recently mapped to the centromeric region of chromosome 9 and contains nine exons, spanning 9 kb (55,56). Several mutations (mostly homogeneous) have been reported (57).
As for PH1, supportive treatment includes confirmation of high fluid intake, administration of crystallization inhibitors, and prevention of complications; there is no rationale for the use of pyridoxine. Kidney transplantation does lead to recurrence, because hyperoxaluria and elevated L-glycerate excretion persist (54). More biochemical data are required before liver transplantation can be recommended (54).
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Atypical PH |
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Conclusions |
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TopIntroductionPH1Treatment in ESRFPH2Atypical PHConclusionsReferences |
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Footnotes |
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References |
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TopIntroductionPH1Treatment in ESRFPH2Atypical PHConclusionsReferences |
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