Primary hyperoxaluria in infants: Medical, ethical, and economic issues

P

Primary hyperoxaluria in infants: Medical, ethical, and economic issues

Pierre Cochat, MD, Paulo C. Koch Nogueira, MD, M. Ayman Mahmoud, MD, Neville V. Jamieson, MD, Jon I. Scheinman, MD, and Marie-Odile Rolland, PhD Objectives: Survey on the current medical approach to and the economic issues affecting infants with primary hyperoxaluria type 1. Methods: Questionnaire to specialized centers worldwide. Results: Seventy-eight infants were identified: 44% were of Muslim origin and 56% were not. The consanguinity rate was 76% and 0%, respectively. Thirty-three percent were treated in developing countries (group 1) and 67% in developed countries (group 2). Initial presentation (4.9 ± 2.8 months) consisted of failure to thrive (22%), urinary tract infection (21%), and uremia (14%). Radiologic findings included nephrocalcinosis (91%), urolithiasis (44%), or both (22%). The diagnosis was based on family history, tissue biopsy, and urine oxalate level in most patients from group 1 and on urine oxalate and glycolate levels, alanine:glyoxalate aminotransferase activity, and DNA analysis in patients from group 2. Therapeutic withdrawal was the final option for 40% of children; financial reasons were given for 10 of 17 patients from group 1 and 0 of 9 from group 2. End-stage renal disease started at 3.2 ± 6.4 years of age and was present in half of the patients at the time of diagnosis. Fifty-two percent of the patients died: 82% in group 1 versus 33% in group 2; 33% of patients who underwent transplantation died versus 71% of those who did not. Conclusion: The management of primary hyperoxaluria type 1 in infants is a major example of the ethical, epidemiologic, technical, and financial challenges that are raised by recessive inherited diseases with early life-threatening onset. In certain circumstances, oxalosis can be regarded as a condition for which therapeutic withdrawal may be an acceptable option. (J Pediatr 1999;135:746-50) Primary hyperoxaluria type 1 is a rare autosomal recessive inherited inborn error of glyoxalate metabolism (1:120,000 live births in France)

caused by a deficient liver-specific enzyme, alanine/glyoxylate aminotransferase. The gene for PH1, AGXT, has been sequenced and located on chro-

From Département de Pédiatrie, Université Claude Bernard, Lyon, France; Giza Pediatric Renal Center, Giza, Egypt; Department of Surgery, University of Cambridge Clinical School, Cambridge, United Kingdom; Department of Pediatrics, Medical College of Virginia of the Virginia Commonwealth University, Richmond, Virginia; University of Kansis Medical Center, Kansas City; and Centre d’Etude des Maladies Métaboliques, Hôpital Debrousse, Lyon, France.

Submitted for publication Jan 15, 1999; revision received July 14, 1999; accepted Aug 19, 1999. Reprint requests: Pierre Cochat, MD, Unité de Néphrologie Pédiatrique, Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/102556

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mosome 2q37.3.1,2 The overall prognosis of the disease is poor because half of the patients reach end-stage renal disease before 5 years of age, and most require combined liver-kidney transplantation.1 The occurrence of PH1 in early childhood raises specific problems because of the severity of the disease in infants, the diagnostic procedures in this age group, and the access to adequate management according to the economic level in each country. We undertook a multicenter retrospective survey of infantile hyperoxaluria in order to precisely delineate both clinical spectrum and management.

AGT ESRD PH PH1 PH2

Alanine: glyoxalate aminotransferase End-stage renal disease Primary hyperoxaluria Primary hyperoxaluria type 1 Primary hyperoxaluria type 2

PATIENTS AND METHODS According to the country of origin and the time of investigation, the diagnosis was made by means of plain x-ray films; renal sonography; tissue biopsy; urine oxalate, urine glycolate, and plasma oxalate levels; AGT activity; DNA analysis; and family history. Renal function was evaluated by determination of plasma creatinine levels. A questionnaire was sent to physicians worldwide who were identified as being responsible for infants with PH. Data were grouped into 8 sections: (1) clinical presentation (family history, consanguinity, gestational age,

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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 6 Table I. Initial symptoms (sometimes associated) of PH1 in infants (n = 78) Failure to thrive Urinary tract infection Uremia Convulsions Metabolic acidosis Anemia Vomiting Macrohematuria Passage of stone Dehydration Polyuria Edema Other*

17 (22%) 16 (21%) 11 (14%) 7 (9%) 7 (9%) 6 (8%) 6 (8%) 4 (5%) 4 (5%) 3 (4%) 2 (3%) 2 (3%) 5 (6%)

*Anorexia, diarrhea, fever, meningitis, respiratory distress.

date of birth, birth weight, gender, country of origin, initial symptoms, age at first symptoms, presence of nephrocalcinosis and/or urolithiasis); (2) initial diagnostic procedures (urine oxalate, urine glycolate, plasma oxalate, and plasma creatinine levels; AGT activity; DNA analysis); (3) conservative treatment (pyridoxine, hydration, crystallization inhibitors); (4) ESRD (age at ESRD, therapeutic withdrawal); (5) dialysis (age, methods); (6) organ transplantation (date and result of isolated kidney, isolated liver, and combined liver-kidney transplantation); (7) outcome (survival, age at last examination/date of death, renal and liver function); (8) comments. Because of a strong influence of ethical and socioeconomic factors on both diagnosis and management, patients were divided into groups according to ethnic background and the economic level of their country. Results are expressed as the mean ± 1 SD (range).

RESULTS Of 86 patients presenting in infancy, 8 were excluded because of diagnosis of PH2 or uncertain diagnosis of PH or because they were free of symp-

Table II. Laboratory assessment of patients with oxalosis (n = 78) according to the country economic level

Urine oxalate Urine glycolate Plasma oxalate Liver AGT DNA analysis Tissue biopsy

Total (% of patients)

Developing countries

Developed countries

44 (56%) 22 (28%) 26 (33%) 28 (36%) 6 (8%) 12 (15%)

20 3 6 2 1 10

24 19 20 26 5 2

Some patients had more than one test; others had no specific biologic investigation.

toms; 78 infants born between 1955 and 1996 (72% in the 1986-1996 period) fulfilled diagnostic criteria and were considered as having PH1. The average gestational age was 39.8 ± 1.0 weeks (n = 42), and birth weight was 3331 ± 494 g (n = 34); male-to-female ratio was 1.1. Ethnic background showed that 34 children (44%) were of Muslim origin (Algeria, Egypt, Jordan, Lebanon, Lybia, Morocco, Pakistan, Saudi Arabia, Syria, Tunisia, Turkey). With respect to the economic level of the country from which the child was referred, 52 (67%) were treated in developed countries (Belgium, Canada, Denmark, France, Germany, Italy, Japan, the Netherlands, Norway, Sweden, Switzerland, United Kingdom, United States of America), and 24 (33%) were treated in developing countries (Brazil, Egypt, Jordan, Lebanon, Morocco, Saudi Arabia, Syria, Tunisia). Positive prenatal diagnosis was available in only one case. Consanguinity was present in 26 of 68 patients (all were of Muslim origin), and there was a positive family history in 26 of 71 patients (37%). Initial symptoms (Table I) were sometimes noted in a single patient; the age at first symptoms was 4.9 ± 2.8 months (range, 0.1-12 months). The laboratory assessment is presented in Table II. At first investigation (sonography, plain abdominal x-ray films), nephrocalcinosis was present in 62 of 69 patients (91%) and urolithiasis in 23 of 52 (44%); both nephrocalcinosis

and urolithiasis were mentioned in 10 of 45 patients (22%). With respect to conservative treatment, pyridoxine had been tested in 41 patients (53%) and was always considered unsuccessful. High fluid intake had been used in 25 patients (32%) and crystallization inhibitors in 25 (32%): citrate in 10, phosphate in 8, and magnesium in 7. Sixty-five patients (83%) had reached ESRD at a mean age of 3.3 ± 6.4 years (range, 0.1-37 years), although ESRD was present in half at the time of diagnosis. Primary or secondary therapeutic withdrawal occurred in 26 of 65 children with ESRD (40%) at a mean age of 1.3 ± 1.7 years (range, 2 months6 years), 71% of patients from developing countries and 17% of those from developed countries. The decision was attributed to parental (16/25), ethical (17/25), and financial (10/25) reasons, which were sometimes associated in a single patient. Financial reasons were only a factor for children in developing countries. In those patients who were first treated by dialysis (n = 58/65, ie, 89% of patients with ESRD), the age at start of renal replacement therapy was 3.2 ± 6.4 years (range, 0.2-37 years). The age at first transplantation was 6.4 ± 7.8 years (range, 0.7-21.0 years). Children who received transplants (n = 33/65, ie, 51% of patients) were divided into 3 groups: (1) among 15 patients with primary isolated kidney transplantation, 8 have died, 4 are alive with a functioning graft, and 747

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THE JOURNAL OF PEDIATRICS DECEMBER 1999

Figure. Relationship between age at ESRD and age at death.

3 have required additional combined liver-kidney transplantation; (2) among 4 patients with preemptive isolated liver transplantation, 1 has died, 2 have stable chronic renal insufficiency, and 1 has required an additional kidney graft; (3) among 14 patients with primary combined liver-kidney transplantation, 2 have died, 11 are alive with functioning grafts, and 1 has chronic renal insufficiency. Fifty-two percent of the patients have died: 82% in developing countries versus 33% in developed countries (P < .05); 33% of those who underwent any kind of transplantation died versus 71% of those who did not (P < .05). There was no relationship between the age at initial symptoms and the age at ESRD, but there was a significant relationship between the age at ESRD and the age at death (Figure).

DISCUSSION PH1 has a variable presentation, ranging from the rapidly progressing infantile form to the more common form of later onset characterized by urolithiasis. Up to 16% of patients with PH1 experience initial symptoms during the first year of life.1,3,4 A review of infantile PH1 in developed countries showed that the diagnosis is usually delayed; most patients are first seen 748

with renal failure before the age of 4 months and die within the first year of life.5 Indeed, fatal outcome has been widely reported from both developed and developing countries.6-9 Pathophysiologic explanations for the clinical presentation of PH1 in infants may be inability of the immature glomerulus to clear the oxalate load, elevated oxalate production caused by a preferred glyoxalate-to-oxalate pathway,10 or high rates of both urine calcium and oxalate excretion.11 In addition, prerenal acute renal impairment (eg, dehydration) might occur in the neonatal period and increase the risk of oxalate deposition in the kidneys, with subsequent irreversible renal failure in patients with hyperoxaluria. All these conditions may be responsible for supersaturation of body fluid, leading to extensive calcium oxalate deposits. The clinical presentation of PH1 in infants is dominated by progressive renal failure together with early nephrocalcinosis, whereas repeated urolithiasis, the hallmark of the classic form in older children and in adults, is usually absent. Such a pattern best fits PH1 because the presentation in PH2 is known to be less aggressive, even with early onset.12,13 Like other recessive hereditary diseases, PH1 is far more frequent in ethnic groups in which consanguinity is common.6,7 This raises critical issues in

those countries with an associated low economic level.14 The practical approach to the assessment of infants with oxalosis in developing countries is currently limited to family history (consanguineous parents, evidence of the disease in siblings, unexplained death in young family members), plain x-ray films, renal sonography, renal or bone biopsy, and calcium oxalate flecks in the retina.6,7,15 The diagnosis of PH1 can be reliably approached by the physical analysis of crystals/urolithiasis and by determination of the urine (or peritoneal fluid in patients with anuria) oxalate and glycolate/creatinine ratio, the normal values of which do not correlate with increasing age.7,15-18 In addition, because there is no circadian rhythm of oxalate excretion, the measurement of the oxalate/creatinine ratio in spot urine samples is suitable for screening neonates and infants.19 Enzymatic diagnosis can be made from a liver biopsy specimen by measuring AGT activity and by assessing the intracellular distribution of immunoreactive AGT protein by immunoelectron microscopy.2 More than 20 mutations in the AGXT gene have been reported; some of them have ethnic specificity reported in Pakistani, Japanese, or Turkish persons.20-22 Prenatal diagnosis with DNA linkage and mutation analysis from a chorionic villus biopsy specimen in the first trimester of pregnancy is a simple and reliable method. However, for both cultural and religious reasons, people living in countries where it could be applied to large kindreds with index cases are often those who are reluctant to agree to both prenatal diagnosis and pregnancy termination. All diagnostic procedures are expensive and require special equipment and training, which cannot be developed in many pediatric centers.14 However, most blood and tissue samples (eg, those obtained for DNA analysis) could be shipped to specialized centers.23 Because of the course of infantile PH1, conservative treatment should be

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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 6 started as early as possible with high fluid intake, urine calcium oxalate crystallization inhibitors, and pharmacologic doses of pyridoxine.2,15 This may delay the onset of renal failure and improve residual glomerular filtration rate.24,25 Unfortunately, such conservative treatment is not commonly used in most developing countries because adapted hydration is challenging in warm climates, crystallization inhibitors and pyridoxine may be expensive and/or not available, and undernutrition is often associated with hyperoxaluria and may increase the risk of stone formation. In any case, hemodialysis or peritoneal dialysis ideally should be avoided,17,26 and the child should be directed either to preemptive liver transplantation or to combined liver-kidney transplantation, according to the progression of renal involvement.2,27-29 However, such an approach is challenging when ESRD is reached before 1 year of age, because of the risks of immunosuppression and the difficulty of placing organs in a small recipient. In fact, for financial and technical reasons, a large number of patients who require renal replacement therapy during the first year of life are first treated with immediate peritoneal dialysis or hemodialysis, sometimes followed by isolated kidney transplantation.7,8,17,30 Although liver transplantation provides the only definite biochemical reconstitution, it raises major ethical, technical, and financial problems. Consequently, isolated kidney transplantation has been revisited and further advocated in both developed31,32 and developing countries.7,33 Poor results have usually been seen,34,35 because this approach does not provide enzyme replacement. The fate of isolated kidney transplantation depends on the total body oxalate load, so that one can speculate that the results should be improved in this age group. On the other hand, the outcome of such a transplant strategy may be influenced by residual AGT activity, which is usually absent in such infantile forms.2,36 In selected

cases in developing countries, isolated kidney transplantation has been proposed as a temporary solution before treating the patient in a specialized center for further combined liver-kidney transplantation.7,37 Such suboptimal conditions therefore require re-evaluation of therapeutic withdrawal, for which the rationale includes ethical, religious, and financial issues.7,17,38,39 In conclusion, infantile PH1 focuses on two opposite issues worldwide: a very rare disease in developed countries where combined liver-kidney transplantation is available and a frequent cause of early ESRD in developing countries where therapeutic withdrawal is widely applied. Consequently, its management is a major example of ethical, epidemiologic, technical, and financial dilemmas, which may be raised by recessive inherited diseases with early life-threatening onset. Oxalosis can therefore be regarded as one of the rare conditions for which therapeutic withdrawal may be an acceptable option according to local necessity. We thank all the physicians worldwide who treated infants with oxalosis and who agreed to provide detailed information: A. Abreu (Sao Paulo, Brazil), E. Al-Sabaan (Riyadh, Saudi Arabia), A. Ayadi (Tunis, Tunisia), J. W. Balfe (Toronto, Ontario, Canada), A. Bensman (Paris, France), A. Bourquia (Casablanca, Morocco), H. Cho (Kanagawa, Japan), P. Cochat (Lyon, France), L. de Pauw (Brussels, Belgium), J. de Ville de Goyet (Brussels, Belgium), P. Fauchald (Oslo, Norway), M. Fischbach (Strasbourg, France), M. F. Gagnadoux (Paris, France), J. W. Groothoff (Amsterdam, The Netherlands), R. Hamed (Amamm, Jordan), G. Herlenius (Stockholm, Sweden), B. Hoppe (Chicago, Illinois, USA), N. Illum (Copenhagen, Denmark), N. V. Jamieson (Cambridge, UK), F. Janssen (Brussels, Belgium), P. Jouvet (Paris, France), A. Kamoun (Tunis, Tunisia), M. J. Krier (Nancy, France), K. Latta (Hannover, Germany), C. Legendre (Paris, France), E. Leumann (Zürich, Switzerland), C. Loirat (Paris, France), A. Mahmoud (Cairo, Egypt), M. A. Mansell (London, UK), D. S. Milliner (Rochester, Minnesota, USA), C. Mourani (Beirut, Lebanon), E. Nathan (Aarhus, Denmark), K. Nishiyama (Shizuoka, Japan), J. B. Otte (Brussels, Belgium), M. C. Ribeiro de Castro

(Sao Paulo, Brazil), G. Rizzoni (Roma, Italy), K. Schärer (Heidelberg, Germany), J. I. Scheinman (Richmond, Va), H. Shiraga (Tokyo, Japan), R. Vandamme-Lombaerts (Leuven, Belgium).

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