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Type 1 Primary Hyperoxaluria in Pediatric Patients: Renal Sonographic Patterns

¹ Department of Pediatric Imaging, Queen Fabiola Children's Hospital, Av. J.J. Crocq, Brussels 1020, Belgium.
² Department of Pediatric Nephrology, Queen Fabiola Children's Hospital, Brussels 1020, Belgium.
³ Department of Medical Imaging, Erasme Hospital, University Clinics of Brussels, 808 Route de Lennik, Brussels 1070, Belgium.

Received March 3, 2004; accepted after revision May 27, 2004.

 
Address correspondence to E. F. Avni (favni{at}ulb.ac.be).

Abstract

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OBJECTIVE. Our aim was to review the sonographic features of type I primary hyperoxaluria in children and to correlate the sonographic patterns with the clinical development of end-stage renal disease (ESRD).

MATERIALS AND METHODS. We performed a retrospective analysis of the clinical and imaging files of 13 patients with type I primary hyperoxaluria who were treated in one institution and of the sonographic patterns and the clinical follow-up reports.

RESULTS. We encountered the following two sonographic patterns: medullary nephrocalcinosis in eight patients and cortical nephrocalcinosis in five patients. The sonographic appearance of cortical nephrocalcinosis is quite specific: a hyperechoic peripheral renal cortex with acoustic shadowing behind it. Medullary nephrocalcinosis is less specific because there are many other causes of hyperechoic pyramids. All patients with medullary nephrocalcinosis developed lithiasis during the course of the disease. All patients with cortical nephrocalcinosis but only two of eight with medullary nephrocalcinosis developed ESRD.

CONCLUSION. Sonography can be used differentiate the two patterns of type 1 primary hyperoxaluria. The cortical nephrocalcinosis type carries a higher risk of developing ESRD.

Introduction

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Type 1 primary hyperoxaluria is a rare autosomal recessive genetic disease caused by a deficient liver enzyme, alanine–glyoxylate aminotransferase. This disorder is characterized by excessive synthesis of oxalic acid (oxalate) and urinary excretion of both oxalate and glycolate. An abnormal deposition of calcium oxalate can occur in bones, joints, nerves, heart, vessels, skin, retinas, and kidneys [1]. In the urinary tract, oxalate is a metabolite excreted by the kidney that induces the death of renal epithelial cells when it is present at excessive concentrations [2–5]. There is a progressive deterioration in renal function resulting in end-stage renal disease (ESRD), requiring dialysis and liver–kidney transplantation. The gene encoding alanine–glyoxylate aminotransferase is located on the locus q37.3 of chromosome 2 [6, 7]. The disease has a variable presentation, and the diagnosis requires the implementation of biologic, enzymatic, genetic, and radiologic procedures. To our knowledge, the sonographic findings in type I primary hyperoxaluria have been infrequently reported.

The purpose of our study was to review the sonographic features of type I primary hyperoxaluria to confirm our hypothesis that the disease may present two sonographic patterns and to eventually correlate the sonographic patterns with the development of ESRD.

Materials and Methods

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Thirteen patients with type I primary hyperoxaluria who underwent sonographic examinations in our institution between 1985 and 2002 were retrospectively evaluated. For all patients, the evaluation addressed the plasma creatinine levels and renal sonographic examinations. Renal sonography was performed using various equipment with 3.75-5.0–MHz curvilinear and 7.5-MHz linear transducers. Patients were divided into two groups on the basis of the sonographic appearance of the kidneys: those with hyperechogenicity of the renal medulla or medullary nephrocalcinosis (Figs. 1 and 2) and those with hyperechogenicity of the renal parenchyma or cortical nephrocalcinosis (Figs. 3 and 4). We further evaluated the degree of medullary nephrocalcinosis: homogeneous hyperechogenicity of all the pyramids (Fig. 1) and heterogenous hyperechogenicity of some or all the pyramids (Fig. 2).

View larger version (151K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1. —10-year-old girl with medullary nephrocalcinosis. Sagittal sonogram of left kidney shows hyperechogenicity of all pyramids.

View larger version (143K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —12-year-old girl with medullary nephrocalcinosis. Sagittal sonogram of right kidney shows that not all pyramids are hyperechoic.

View larger version (86K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —2-week-old boy with cortical nephrocalcinosis. Sagittal sonogram of right kidney shows that proximal superficial cortex appears hyperechoic compared with deeper cortex. Note lack of corticomedullary differentiation.

View larger version (102K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4. —2-year-old boy with cortical nephrocalcinosis. Sagittal sonogram shows right kidney. Note striking hyperechogenicity of cortex adjacent to liver and acoustic shadowing in deeper areas.

For the purpose of correlation between the sonographic patterns and ESRD, we made a comparison for each year of follow-up between the worst level of plasma creatinine and the simultaneous sonographic appearance. Three patients were excluded from this part of the study: one died 1 year after the diagnosis, and the remaining two corresponded to patients recently diagnosed. Urolithiasis was considered a complication of the disease.

Results

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Seven boys and six girls, ranging from 5 to 23 years old, were studied. The age at diagnosis ranged between 2 days and 14 years (mean age, 4.5 years). The 13 patients belonged to seven different families. For eight patients (61.5%), there was a family history of consanguinity (seven with medullary nephrocalcinosis and one with cortical nephrocalcinosis). In one family, both cortical nephrocalcinosis and medullary nephrocalcinosis patterns were present.

The sonographic examinations revealed five patients (38%) with cortical nephrocalcinosis (Figs. 3 and 4) and eight patients (61.5%) with medullary nephrocalcinosis (Figs. 1 and 2). Urolithiasis was already present at diagnosis in one patient (8%). This rate increased to 62% during the follow-up period. At one stage or another, all patients with medullary nephrocalcinosis had urolithiasis; only two of the five patients with cortical nephrocalcinosis developed urolithiasis. The plasma creatinine level increased from an initial mean of 1.7 mg/dL (range, 0.8–4.6 mg/dL) to a mean of 4 mg/dL (range, 0.8–12 mg/dL) during the follow-up period. The creatinine levels were higher in patients with cortical nephrocalcinosis than in those with medullary nephrocalcinosis. Seven patients (five with cortical nephrocalcinosis and two with medullary nephrocalcinosis) developed ESRD (Table 1).

During follow-up, the patients with cortical nephrocalcinosis had no significant variation of renal function up to the time of liver–kidney transplantation. For the patients with medullary nephrocalcinosis, there was a direct relationship between the creatinine level abnormalities and the increase of the nephrocalcinosis or the presence of obstructive urolithiasis. Five patients (four with cortical nephrocalcinosis and one with medullary nephrocalcinosis) underwent combined liver–kidney transplantation.

Discussion

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Type I primary hyperoxaluria is a rare metabolic entity (1:120,000 live births in France) in which the conversion of glyoxylate to glycine is impaired because of a deficiency in the hepatic alanine-glyoxylate aminotransferase levels [2, 4, 8]. Because of this deficiency, the glyoxylate is converted into oxalate that accumulates in various tissues (heart, muscles, kidneys, and so forth). The excess oxalate is excreted through the kidneys, and the tubules of the kidneys are progressively but definitively damaged. The disease is more frequent in ethnic groups in which consanguinity is common [4, 5]. Consanguinity was present in 61.5% of our patients and in 38% in a recent French study of 68 patients [2].

The clinical presentation comprises three forms: The neonatal form is severe and includes failure to thrive and renal failure progressing rapidly, the infantile form is milder and is diagnosed during family screening, and the late childhood form is discovered through the detection of nephrocalcinosis or urolithiasis or both [2, 4].

The diagnosis of type I primary hyperoxaluria can be approached by analysis of plasma oxalate, urinary glycolate, and oxalate levels. An enzymatic study obtained from liver biopsy can quantify alanine-glyoxylate aminotransferase activity. An antenatal diagnosis is possible because of the molecular analysis of the different mutations [6, 7].

The natural outcome of the disease is ESRD. In the literature, the percentage of type I primary hyperoxaluria as a cause of ERSD varies according to geographic region: 13% in a Tunisian series and 0.3–2.7% in European studies [6, 8, 9]. The purpose of treatment is to delay as much as possible renal transplantation and to prevent complications.

Our study confirms our preliminary hypothesis that there are two sonographic patterns of type 1 primary hyperoxaluria, one for cortical nephrocalcinosis and one for medullary nephrocalcinosis, and that the two patterns may be present in the same family. In our series, medullary nephrocalcinosis was the most common presentation (61.5%).

The sonographic pattern of cortical nephrocalcinosis is quite specific: diffuse markedly hyperechoic peripheral renal cortex with possible global acoustic shadowing without corticomedullary differentiation (Figs. 3 and 4). Other causes of global cortical hyperechogenicity include cortical necrosis, Alport's syndrome, renal toxicity (due to medication and infection), congenital nephrotic syndromes, hemolytic uremic syndrome, and some infections. In two of our patients, the cortical hyperechogenicity and acoustic shadowing increased with age (Figs. 3 and 4). This differentiation could be an interesting feature that should be confirmed by further studies. In type 1 primary hyperoxaluria, the marked hyperechogenicity is probably directly related to the amount of oxalate of calcium deposits (as shown on CT) [10] (Fig. 5).

View larger version (130K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5. —2-week-old boy with type I primary hyperoxaluria with cortical nephrocalcinosis. Unenhanced CT scan shows spontaneous hyperdensity of cortex.

The sonographic pattern of medullary nephrocalcinosis is less specific because the differential diagnosis is much wider (Figs. 1 and 2). Hyperechogenicity of the pyramids can be associated with entities with or without hypercalciuria. The diagnosis is based on the results of specific biologic and genetic studies whenever pertinent.

The medullary nephrocalcinosis pattern of type 1 primary hyperoxaluria must be included in the differential diagnosis of hypercalciuric nephrocalcinosis. Diseases with a specific association of hypercalciuria and nephrocalcinosis are numerous, and the differential diagnosis cannot be based on the sonographic pattern alone [10–14].

In our study, the correlation between the type of nephrocalcinosis and ESRD reveals that ESRD is more frequently associated with cortical nephrocalcinosis (five of five patients) than with medullary nephrocalcinosis (two of eight patients) and that renal failure develops more rapidly with cortical nephrocalcinosis (mean age, 3.7 years) than with medullary nephrocalcinosis (mean age, 7 years). On the contrary, urinary lithiasis develops more frequently when medullary nephrocalcinosis is observed. A hypothesis explaining this difference could be that the cellular damage induced by cortical nephrocalcinosis impairs the renal function more rapidly by the more diffuse and extensive oxalate deposits, whereas in medullary nephrocalcinosis, ESRD develops only when medical therapy cannot reverse the increased medullary oxalate deposits and the deleterious effects of obstructive urinary lithiasis.

In summary, our study of 13 patients shows the importance of sonography in type I primary hyperoxaluria. Discrimination of the two patterns is important because of the different evolution of the disease and the different treatment strategies required. Sonography appears more specific for the diagnosis of cortical nephrocalcinosis in type 1 primary hyperoxaluria, and the evolution towards ESRD is more rapid.

References

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