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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
RENAL DATA FROM THE ARAB WORLD  
Year : 2012  |  Volume : 23  |  Issue : 2  |  Page : 385-390
Primary hyperoxaluria type 1 in Tunisian children


1 Department of Pediatric Nephrology, Charles Nicolle Hospital, Tunis, Tunisia
2 Deparment of Pediatric Surgery, Habib Thameur Hospital, Tunis, Tunisia
3 Department of Clinical Biochemistry, Charles Nicolle Hospital, Tunis, Tunisia

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Date of Web Publication28-Feb-2012
 

   Abstract 

To determine the clinical, biological, and radiological futures of primary hyper-oxaluria type 1 in Tunisian children, we retrospectively studied 44 children with primary hyper-oxaluria type 1 who were treated in our center from 1995 to 2009. The diagnosis was established by quantitative urinary oxalate excretion. In patients with renal impairment, the diagnosis was made by infrared spectroscopy of stones or kidney biopsies. The male-to-female ratio was 1:2. The median age at diagnosis was 5.75 years. About 43% of the patients were diagnosed before the age of five years with initial symptoms dominated by uremia. Four patients were asymptomatic and diagnosed by sibling screenings of known patients. Nephrocalcinosis was present in all the patients; it was cortical in 34%, medullary in 32%, and global in 34%. At diagnosis, 12 (27%) children were in end-stage renal disease. Pyridoxine response, which is defined by a reduction in urine oxalate excretion of 60% or more, was obtained in 27% of the cases. In the majority of patients, the clinical expression of primary hyperoxaluria type 1 was characterized by nephrocal-cinosis, urolithiasis, and renal failure; pyridoxine sensitivity was associated with better outcome.

How to cite this article:
Gargah T, Khelil N, Youssef G, Karoui W, Lakhoua MR, Abdelmoula J. Primary hyperoxaluria type 1 in Tunisian children. Saudi J Kidney Dis Transpl 2012;23:385-90

How to cite this URL:
Gargah T, Khelil N, Youssef G, Karoui W, Lakhoua MR, Abdelmoula J. Primary hyperoxaluria type 1 in Tunisian children. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2014 Oct 30];23:385-90. Available from: http://www.sjkdt.org/text.asp?2012/23/2/385/93188

   Introduction Top


Primary hyperoxaluria type 1 (PH1) is a rare autosomal-recessive inherited disorder caused by mutations in the alanine: glyoxylate amino-transferase (AGT) gene, which is an important enzyme in the detoxification of glyoxylate. [1] The insufficient AGT activity in peroxisomes leads to increased conversion of glyoxylate to oxalate, a toxic compound normally cleared by the kidney. [2] The excess oxalate combines with calcium to form an insoluble calcium oxalate. Kidney, which is the sole route of excretion of calcium oxalate, is the primary target organ for the disease process. The deposition of this subs­tance in the kidney parenchyma and urinary tract results in renal failure, which in turn leads to accumulation of oxalate of soft tissues and bone. [3],[4]

In Tunisia, PH1 appears to be a common cause of nephrocalcinosis and may be an im­portant cause of end-stage renal disease in our population. [5],[6]

We report in this study our experience of Tunisian patients with PHI to determine the role of early diagnosis, aggressive medical ma­nagement, pyridoxine therapy, and organ trans­plantation in the prevention and treatment of affected patients.


   Subjects and Methods Top


This a retrospective study of 44 children with PH1 who were assessed in our department bet­ween 1995 and 2009. An information sheet was prepared containing the following data: cli­nical presentation (family history, consanguinity, initial symptoms, presence of nephrocalcinosis and/or urolithiasis), initial diagnostic procedure, treatment and outcome. Estimated glomerular filtration rate (GFR) was calculated using the previously validated Schwartz formula. [7]

The classification of the stages of chronic kidney disease was as follows: Stage 1: mild reduction in GFR (70-80 mL/min/1.73 m 2 )

Stage 2: moderate reduction in GFR (30-70 mL/min/1.73 m 2 )

Stage 3: severe reduction in GFR (15-30 mL/min/1.73 m 2 )

Stage 4: advanced kidney failure (10-15 mL/min/1.73 m 2 )

Stage 5: kidney failure (GFR<10 mL/min/1.73 m 2 ).

In the presence of a normal GFR, the diag­nosis of PH1 was confirmed by either mea­suring urinary oxalate excretion in 24-hour urine collections, or by spot urine oxalate/crea-tinine. Normal reference values are summa­rized in [Table 1].
Table 1: Normal reference values of oxaluria, glycoluria, and oxalate: creatinine ratio.

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Urine oxalate was determined by a kit me­thod quantitative enzymatic assay of oxalate by oxalate oxidase. Urine glycolate was de­tected qualitatively by gas chromatography.

In the presence of chronic renal failure, the diagnosis was established either by infrared spectroscopy of stones or by a kidney biopsies, or when the clinico-radiological presentation was typical.

All patients were evaluated by renal ultra­sound for diagnosis of nephrocalcinosis and/or nephrolithiasis. Nephrocalcinosis has been classified according to Dick's method. [8]

Medical management consisted of pyridoxine 10-20 mg/kg/day in two divided doses in all the patients. Testing of the clinical vitamin B6 response was evaluated by measuring urine oxalate excretion before and three months after treatment in patients with GFR more than 50 mL/min/1.73 m 2 . This test was unreliable in patients with moderate to advanced renal insufficiency. A response was considered as favorable when the excretion rates decreased by two-thirds compared to the initial values.

Patients with normal GFR were instructed to maintain high fluid intake. Magnesium sulfate was administered in patients with GFR more than 50 mL/min/1.73 m 2 .


   Statistical Analysis Top


Four different parameters in relation to out­come were investigated: age, nephrocalcinosis at diagnosis, GFR at diagnosis, level of urinary oxalate, and pyridoxine responsiveness. The statistical analysis was conducted using Stat View software 5.0. Categorical variables were compared using the unpaired student's "t" test. Nominal variables were compared using a chi-square test. The level of statistical significance was set at P < 0.05.


   Results Top


The study patients comprised 24 (54.5%) boys and 20 (45.5%) girls. Thirty patients belonged to 20 different families. A family history of consanguinity was positive in 40 (90%) pa­tients. Most of the children lived in central and southern Tunisia. The median age at diagnosis was 5.75 years (range 3 months-14 years). About 43% of the patients were diagnosed as PH1 before the age of five years. Initial symp­toms and signs are summarized in [Table 2]. Four patients were asymptomatic and diag­nosed by sibling screening of known patients with HPI. The sonographic examinations revealed 15 (34%) patients with cortical nephrocalcinosis, 14 (32%) patients with medullary nephrocal-cinosis, and 15 (34%) patients with both cor­tical and medullary nephrocalcinosis [Figure 1]. In five patients, ultrasound was not helpful in the diagnosis of nephrocalcinosis and dis­closed global cortical hyperechogenicity with­out urolithiasis. CT scan confirmed the exis­tence of cortical nephrocalcinosis in all the cases [Figure 2]. Urolithiasis was already present at diagnosis in 22 (50%) patients. It was associated with cortical nephrocalcinosis in five patients, with the medullary nephrocal-cinosis in ten patients, and with the mixed nephrocalcinosis in seven patients. No statis­tically significant correlation was found bet­ween the presence of nephrolithiasis and topo­graphy of nephrocalcinosis.
Figure 1: Kidney sonography: Global nephrocalcinosis in a patient with hyperoxalosis.

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Figure 2: Unenhanced CT scan showing a spontaneous hyperdensity of cortex in a patient with hyperoxalosis.

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The diagnosis of PHI was made by quanti­tative urinary oxalate excretion in 19 patients, where the mean excretion rate was 1.13 ± 0.28 mmol/1.73 m 2 /24 h. In three patients, the diag­nosis was confirmed by spot urine oxalate/ creatinine mmol ratios, with a frankly patho­logical ratio. Glycolic aciduria was present in all 12 patients tested for it. In 12 patients with ESRD, the diagnosis was established by kid­ney biopsies in nine (in one case it was post­mortem) [Figure 3]. In three patients, the diag­nosis was confirmed by the family history of PH1, clinico-radiological presentation, and by infrared spectroscopy of stones.
Figure 3: Renal biopsy: view under polarized light: the deposits are strongly birefringent.

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Table 2: Initial symptoms and associations of primary type 1 hyperoxalosis.

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At diagnosis, 12 (27%) children were in ESRD. Nine among them died due to complications of systemic oxalosis. Three patients continued on hemodialysis. Two children in severe reduc­tion in GFR reached ESRD after an average of 13 months. Among three children with mode­rate renal impairment, two progressed to ESRD. Twenty-two patients with normal GFR and five with mild chronic renal failure were treated with the medical regimen described and maintained normal or mildly impaired renal function during up to five years in 52% of the cases. There was a statistically signi­ficant correlation between progression to ESRD and cortical nephrocalcinosis (P< 0.0001).

Response to pyridoxine was evaluated in 22 patients; only six (27%) patients were pyri-doxine sensitive and maintained normal renal function.


   Discussion Top


PH1 is caused by a functional deficiency of the liver-specific, peroxisomal, pyridoxal phos­phate-dependent enzyme alanine: AGT. Nu­merous mutations and polymorphisms in the gene encoding AGT have been identified, but in only a few cases has the causal relationship between genotype and phenotype actually been demonstrated. [9] The prevalence of the disease has been well documented in developed coun­tries such as France and Switzerland, where the prevalence of 2.5 per million population (PMP) and 3.9 PMP was found, respectively. [2],[10] In our country, it is difficult to estimate the prevalence. We believe that the observed pre­valence rate is still an under-estimation of the true prevalence, since the difficulty of achie­ving systematic family screening and the vague initial symptoms can easily results in a delay or absence of screening for PH1. The clinical symptoms of PH1 are the con­sequences of excessive urinary excretion of the insoluble calcium oxalate crystals, which lead to nephrolithiasis and/or nephrocalcinosis. Uremia, gross hematuria, and urinary tract in­fection are the most frequent signs reported in our patients. They are comparable to those described in literature. [3] However, many pa­tients remain asymptomatic for a long time or present with nonspecific symptoms such as failure to thrive, anemia or dehydration. These symptoms were often not adequately under­stood, and therefore the opportunity for timely diagnosis is usually missed. Accordingly, ESRD may occur as the first presenting sign of PHI, and it is present in 40% of pediatric patients; [10] in our study, ESRD was present in 27% of the patients. Some patients reach ESRD within the first year of life, while others maintain satis­factory kidney function till middle age. This variability has not been satisfactorily explained and is only partially influenced by genotype or other factors such as degree of hyperoxaluria. [11]

Early diagnosis of PH1 is of vital importance so that treatment can be initiated as soon as possible. The combination of both clinical and sonographic signs is a strong argument for PH1: the association of renal calculi, nephro-calcinosis and renal impairment besides family history. In patients with normal renal function, the diagnosis can be approached by analysis of plasma oxalate, urinary excretion of oxalate, and urinary glycolate. [12] In patients with im­paired renal function, definitive diagnosis may sometimes require the measurement of AGT activity in liver tissue. [13] This enzymatic study is unavailable in our country; we replaced it with renal biopsies in nine patients. This diag­nostic procedure has been used elsewhere by several authors in patients with ESRD. The ty­pical appearance is an extensive oxalate crystal deposition viewed under a Polaroid filter as we have observed in our patients. [14]

The antenatal diagnosis of PH1 is possible. Various strategies have been adopted inclu­ding analysis of DNA extracted from fetal cells obtained by amniocentesis usually per­formed at approximately 15-18 weeks of ges­tation or chorionic villus sampling at appro­ximately 10-12 weeks of gestation. [3] Indepen­dent of diagnostic value, mutation analysis may provide information on pyridoxine res­ponsiveness, on complex enzyme phenotype, and sometimes on clinical prognosis. [15]

The natural outcome of the PH1 is ESRD. [10],[16] The percentage of this disease as a cause of ESRD varies according to the geographic region. In Tunisia, PHI is more common than other countries; it represents the cause of ESRD in 13% of pediatric patients compared to only 0.3% in Europe. [3] The poor prognosis is mainly related to the marked hyperecho-genicity of renal parenchyma, which is directly related to the amount of oxalate of calcium deposit. Kidney failure is more frequently associated with cortical than medullary neph-rocalcinosis. In our study, we found a corre­lation between ESRD and cortical nephro-calcinosis (P< 0.001). Nevertheless, urinary lithiasis develops more frequently when medullary nephrocalcinosis is observed. These findings were also comparable with those of Diallo's study. [17]

The definitive treatment for PH1 is liver transplantation to replace the functional defect of hepatic AGT. However, this requires com­plete removal of the patient's otherwise nor­mal liver, exposing the patient to the risks of the transplant procedure, as well as the risks of life-long immune suppression. [18]

In 30-50% of PH1 patients, reduction in urine oxalate excretion can be achieved by treatment with pharmacological doses of pyri-doxine through enhancement of AGT enzyme activity. [19] In our patients, the response to pyri-doxine was around 25%. This response rate is much lower than that reported in the literature probably because of genetic factors and/or poor adherence to treatment. Other treatment measures, directed to reduction in crystal and stone formation, include high fluid intake to reduce urine oxalate concentration and oral medications that inhibit calcium oxalate crys­tal formation, specifically citrate and phos-phate. [20] All of these modalities have been in use for more than 30 years. Though long-term outcomes have improved with earlier diag­nosis and currently available treatment, renal failure nonetheless still develops in 70% of the patients. More effective treatments are still required. Promising new directions using mo­lecular chaperones, oxalate degrading bacteria, and exploitation of oxalate transport physio­logy are in various stages of investigation. [3]

In conclusion, PHI is a heterogeneous disease with high variations of age of first presentation and progression into renal failure and subse­quent systemic oxalosis. Early diagnosis is im­perative, but is often delayed or overlooked. Effective therapy to prevent progression is still required.

 
   References Top

1.Danpure CJ. Metabolic and clinical hetero­geneity of primary hyperoxaluria type 1. Am J Kidney Dis 1991;17:366.  Back to cited text no. 1
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3.Cochat P, Liutkus A, Fargue S, Basmaison O, Ranchin B, Rolland MO. Primary hyperoxa-luria type 1: still challenging. Pediatr Nephrol 2006;21:1075-81.  Back to cited text no. 3
    
4.Bacchetta J, Fargue S, Boutroy S, et al. Bone metabolism in oxalosis: a single-center study using new imaging techniques and biomarkers. Pediatr Nephrol 2010;25:1081-9.  Back to cited text no. 4
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5.Kammoun A, Lakhoua MR. End stage renal disease of the Tunisian child: epidemiology, etiology and outcome. Pediatr Nephrol 1996; 10:479-82.  Back to cited text no. 5
    
6.Marrakchi O, Belhaj R, Bahlous A, et al. Urinary stones in Tunisian children: based on series of 187 cases Prog Urol 2008;18(13): 1056-61.  Back to cited text no. 6
    
7.Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 34:571-590.  Back to cited text no. 7
    
8.Dick PT, Shuckett BM, Daneman A, Kooh SW. Observer reliability in grading nephro-calcinosis on ultrasound examinations in child­ren. Pediatr Radiol 1999;29:68-72.  Back to cited text no. 8
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9.Williams EL, Acquaviva C, Amoroso, et al. Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum Mutat 2009;30:910-7.  Back to cited text no. 9
    
10.Von Woerden SC, Groothoff JW, Wanders RJ, Davin JC, Wijburg FA. Primary hyperoxaluria type 1 in Netherlands: prevalence and out­come. Nephrol Dial Transplant 2003;18:273-9.  Back to cited text no. 10
    
11.Coulter-Mackie MB. Preliminary evidence for ethnic differences in primary hyperoxaluria type 1 genotype. Am J Nephrol 2005;25:264-8.  Back to cited text no. 11
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12.Belhadj R, Hayder N, Gargah T, et al. Bio­chemical and molecular diagnosis of primary hyperoxaluria type 1. Pathol Biol 2011;59(4): e97-102.  Back to cited text no. 12
    
13.Amoroso A, Pirulli D, Florian F, et al. AGXT gene mutations and their influence on clinical heterogeneity of type 1 primary hyperoxaluria. J Am Soc Nephrol 2001;12:2072-9.  Back to cited text no. 13
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14.Khoo JJ, Pee S, Kamaludin DP..DInfantile pri­mary hyperoxaluria type 1 with end stage renal failure. Pathology 2006;38:371-4.  Back to cited text no. 14
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15.Leumann E, Hoppe B. Primary hyperoxaluria type 1: is genotyping clinically helpful? Pediatr Nephrol 2005;20:555-7.  Back to cited text no. 15
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16.Milliner DS, Wilson DM, Smith LH. Pheno-typic expression of primary hyperoxaluria: comparative features of types I and II. Kidney Int 2001;59:31-36.  Back to cited text no. 16
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17.Diallo O, Janssens F, Hall M, Avni EF. Type 1 Primary hyperoxaluria in pediatric patients: renal sonographic patterns. AJR Am J Roentgenol 2004;183:1767-70.  Back to cited text no. 17
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18.Cox KL, Filler G, Salvatierra O Jr, Esquivel CO. 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;76:1458-63.  Back to cited text no. 18
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19.Monico CG, Rossetti S, Olson JB, Milliner DS. Pyridoxine effect in type I primary hyper-oxaluria is associated with the most common mutant allele. Kidney Int 2005;67:1704-9.  Back to cited text no. 19
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20.Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant 2005;20:1525-9.  Back to cited text no. 20
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Correspondence Address:
Tahar Gargah
Department of Pediatric Nephrology, Charles Nicolle Hospital, Boulevard 9 Avril, Bab Saadoun, Tunis 1007
Tunisia
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PMID: 22382246

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