Nephrol Dial Transplant (2001) 16: 2236–2239
Preliminary Report
Bone mineral density in children with primary hyperoxaluria type I Barbara Behnke, Markus J. Kemper, Hans-Peter Kruse1 and Dirk E. Mu¨ller-Wiefel Departments of Paediatric Nephrology and 1Medical Osteology, University Hospital Eppendorf, Hamburg, Germany
Abstract Background. In primary hyperoxaluria type I (PH 1), hepatic overproduction of oxalate leads to its deposition in various organ systems including bone (oxalosis). To evaluate skeletal status non-invasively in PH 1 we measured bone mineral density (BMD). Methods. Peripheral quantitative computed tomography of the distal radius was performed in 10 children with PH 1 (mean chronological age 9"3.1, mean skeletal age 8.3"3.0 years): seven were on conservative treatment (CT) including one patient after pre-emptive liver transplantation (PH1-CT) and three were studied with end-stage renal disease on peritoneal dialysis (PH1-ESRD). Results. Mean trabecular bone density (TBD) was significantly increased in PH1-ESRD compared with both age-matched healthy and uraemic controls (65227 vs 168"63 and 256"80 mgucm3; P-0.002 and P-0.007, respectively), while cortical bone density (CBD) was elevated to a lesser degree (517"23 vs 348"81 vs 385"113 mgucm3; P-0.02 and P-0.04, respectively). In PH 1, CBD and, even more so, TBD were significantly correlated with serum creatinine (r s0.91 and rs 0.96, P-0.0001, respectively) and plasma oxalate levels (r s0.86 and rs 0.94, P-0.001 and P-0.0001, respectively). In children with PH 1 and normal glomerular function, both CBD and TBD were comparable with healthy controls. Conclusion. These preliminary data suggest that in PH 1 BMD is significantly increased in ESRD, probably due to oxalate disposal. Measurement of BMD may be a valuable and non-invasive tool in determining and monitoring oxalate burden in this disorder. Keywords: bone mineral density; primary hyperoxaluria type I; pQCT; skeletal oxalate deposition
Correspondence and offprint requests to: Dr Markus J. Kemper, Paediatric Nephrology, University Children’s Hospital, CH-8032 Zurich, Switzerland. Email:
[email protected] #
Introduction In primary hyperoxaluria type I (PH 1) hepatic deficiency or mistargeting of alanine : glyoxylate aminotransferase (AGT) leads to loss of glyoxylate amination to glycine. The accumulated glyoxylate is oxidized to oxalate, which cannot be further metabolized and is, therefore, mainly excreted by the kidney (hyperoxaluria). This leads to urinary precipitation of calcium oxalate, resulting in urolithiasis and often nephrocalcinosis. Progressive renal insufficiency with uraemia frequently occurs in childhood or early adulthood although early diagnosis and conservative treatment (CT) can improve long-term prognosis of patients w1–3x. If end-stage renal disease (ESRD) is reached, the only curative therapy of PH 1 remains combined liver– kidney transplantation w4x. Pre-emptive liver transplantation can also cure the metabolic defect in PH 1 and may prevent oxalate deposition if performed early enough w5,6x. With a decreasing glomerular filtration rate (GFR), plasma oxalate levels markedly increase resulting in extrarenal tissue deposition of calcium oxalate crystals (oxalosis). Major sites of deposition include bone, bone marrow, heart, blood vessels, cartilage, and periarticular soft tissue w1x. With prolonged survival of these patients the consequences of oxalate deposition into extrarenal tissue, especially into bone, become a major problem. Oxalosis-related bone disease, which is the consequence of both renal osteodystrophy and oxalate deposition, leads to severe bone pain, growth dysfunction, deformities, and pathological fractures w7–9x. Serological parameters of mineral metabolism are often altered because of renal insufficiency. X-ray findings of skeletal abnormalities include osteosclerosis as well as osteopenia and a variety of other changes (dense metaphyseal bands, submarginal metaphyseal lucency, sclerosis of the adjacent diaphysis, cystic bone changes, subperiosteal resorption, coarsed or blurred trabecular pattern), all of them being unable to reflect accurately the severity of bone involvement of PH 1. Bone biopsies from the iliac crest have been regarded as diagnostic gold standard and show oxalate crystals that are isolated or grouped in clusters, forming star-like or rosette figures, and are often surrounded
2001 European Renal Association–European Dialysis and Transplant Association
BMD in children with primary hyperoxaluria type I
by a granulomatous reaction w10,11x. However, bone biopsies are an invasive procedure and, therefore, not suitable for clinical routine follow-up, especially in paediatric patients. Previous studies have clearly demonstrated that bone densitometry by means of peripheral quantitative computed tomography (pQCT) is a reliable, reproducible, and non-invasive method to detect and follow skeletal disorders in the clinical routine of paediatric patients, especially with chronic renal disease including the study of effects of therapeutical approaches w12,13x. We therefore studied bone mineral density (BMD) and skeletal status in 10 paediatric patients with PH 1 at various stages of renal function in order to assess the value of bone densitometry in assessing oxalate-related bone disease.
Patients and methods We measured BMD in all 10 children with PH 1 (five males and five females) treated in our department. Diagnosis of PH 1 was made by measuring the typical urinary metabolites (oxalate, glycolate) and plasma oxalate. Hepatic AGT deficiency was documented in seven patients and in one patient the diagnosis was confirmed by linkage analysis. Mean chronological age of PH 1 patients was 9.0"3.1 (range 3.8–12.8) years and mean skeletal age 8.3"3.0 (range 3.5–12.5) years. Seven patients were treated conservatively (CT) (300–600 mgum2uday pyridoxine and 0.5 mEqukguday citrate orally) and six of these had a normal renal function (median creatinine 0.8 (range 0.6 –1.0) mgudl); one patient in this group was studied 49 months after pre-emptive LTX with a serum creatinine of 2.4 mgudl (calculated GFR 24 mluminu1.73 m2 (for description of this patient see ref. w6x)). Three children were studied in ESRD on peritoneal dialysis (mean time on dialysis 19.3"8.1 (range 12–28) months). For comparison, BMD was also measured in eight healthy children with normal kidney function serving as healthy controls (mean age 12.2"5.7 (range 3–16) years). In addition, 19 children with ESRD on dialysis (continuous ambulatory peritoneal dialysis n s 14, haemodialysis n s 5) without PH 1 were studied as uraemic controls (mean age 12.2"5.2 (range 2.5 –19.5) years; mean skeletal age 10.8"5.1 (range 2.0–19.0) years; mean time on dialysis 18.8"14.5 (range 1– 41) months). Serum creatinine was measured by a spectrophotometric method, serum calcium and phosphate by standard colorimetric methods, the intact parathyroid hormone (PTH) by means of a monoclonal radioimmunoassay (Elsa-PTH, Schering, CIS Diagnostik GmbH), and bone alkaline phosphatase (BAP) with the Tandem1 Ostase-Test as previously described w14x. X-ray of the non-dominant hand was performed in all patients to establish bone age (according to Greulich-Pyle). X-rays of other sites of the skeleton were performed, e.g. in case of bone pain. Bone biopsies of the iliac crest were not done. BMD of the distal radius (of the non-dominant arm) was measured by means of pQCT (XCT 900, Stratec, Germany). At the beginning of each examination a digital radiography was carried out to define the measuring site. A single slice of 3 mm thickness was taken from 72 different angles at a distance of 4% of the total radius length proximal to the
2237
epiphyseal growth plate. After detecting the outer bone contour, the cross-sectional area of the radius was determined and bone density distribution was analysed selectively: total bone density (BD), trabecular (TBD; 45% core area of the bone cross-section), and cortical bone density (CBD; total minus trabecular area). Results were expressed in mgucm3 (volume-equivalent). The local radiation exposure is low (0.1 mGy) and the coefficient of variation -1% w15x. Values are given as means"standard deviation (SD) unless stated otherwise. The assessment of statistical significance was performed by Mann–Whitney U test. For analysis of relationships we used Pearson’s coefficient of correlation; a P-value -0.05 was considered to be statistically significant.
Results When patients with PH 1 were analysed together, mean TBD and CBD were not statistically different compared with healthy controls (Table 1). However, when patients with PH 1 were subdivided according to renal function, CBD and especially TBD were strongly elevated in PH 1 patients with ESRD, even when compared with non-PH1-ESRD patients, while in PH1-CT values remained comparable with controls (Table 1). CBD as well as TBD significantly correlated with serum creatinine and plasma oxalate (Figures 1 and 2). No significant differences between groups and correlation of TBD or CBD with serological parameters of bone metabolism (total alkaline phosphatase and BAP, intact PTH, serum calcium and phosphate and calcium 3 phosphate product) could be found (Table 2).
Discussion This is the first study evaluating skeletal status in PH 1 non-invasively by BMD. Because of the rarity of this disorder only a small number of patients could be investigated and longitudinal data are not available yet. Furthermore, inclusion of a patient after preemptive liver transplantation, inclusion of uraemic controls on haemodialysis as well as age differences between study and control group may have had a certain impact on results. Despite these limitations, our data demonstrate significant elevation of BMD in children with PH 1 and concomitant ESRD that indicate a potential value of regular bone densitometry in this disorder. Interestingly, at normal GFR, BMD in children with PH 1 is comparable with healthy controls. The distinct increase of CBD and even more so of TBD in PH 1 patients with ESRD are likely to be caused by oxalate disposal, as is suggested by the significant correlation to plasma oxalate levels and renal function. A parallel determination of bone oxalate content needs to be considered in future studies to clearly prove the association between increased BMD and oxalate disposal. In addition to oxalate quantification
2238
B. Behnke et al.
Table 1. Bone densitometry results measured by pQCT in study groups
TBD CBD
PH 1 all (n s 10)
PH1-CT (n s 7)
PH1-ESRD (n s 3)
Healthy controls (n s 8)
ESRD-controls (n s 19)
305"215 (126.8–240.6) 362"105 (234.4 –541.5)
172"49 (126.8 – 670.3) 316"62 (234.4 –397.0)
652"27 (618.9 – 670.3)a,b 517"23 (494.2–541.5)d,e
168"63 (120.7–307.2) 348"81 (229.3 – 480.2)
256"80 (144.3 – 441.4)c 385"113 (110.4 – 619.2)
Values are given as mean"SD (range). aP-0.002 vs heathy controls, bP-0.007 vs ESRD-controls, cP-0.02 vs healthy controls, dP-0.02 vs healthy controls, eP-0.04 vs ESRD-controls.
Fig. 1. Correlation of TBD with plasma oxalate and serum creatinine.
Fig. 2. Correlation of CBD with plasma oxalate and serum creatinine.
techniques, conventional bone biopsies would also help to study the detailed impact of oxalate deposition on BMD, especially TBD, e.g. localization of oxalate crystals within bone marrow spaces or between trabeculae and inside calcified bone matrix. The significant increase of both TBD and CBD in PH1-ESRD over uraemic control patients on dialysis treatment and the lack of influence of established parameters of bone biochemistry including hyperparathyroidism in our patients, however, encourage us to interpret our findings as a consequence of oxalate disposal in ESRD. Although the dynamics of oxalate deposition in PH 1 are not completely understood, there is evidence that at reduced GFR, especially in ESRD, this deposition increases massively w16x. Decreases of GFR result in an increase of plasma oxalate and plasma oxalate supersaturation, and results in the expansion of the insoluble oxalate pool. In adults a plasma oxalate of 40–50 mmolul has been correlated with an increase of
the oxalate supersaturation w17x, but recently Hoppe et al. w18x have shown increases in the oxalate supersaturation already at normal GFR, indicating that oxalate deposition might occur much earlier. In this respect regular evaluation of BMD could help to define the set point at which GFR and plasma oxalate levels of oxalosis-related bone disease develops. Routine X-ray investigations show only advanced oxalate-induced changes that cannot be quantified objectively. Repeated bone biopsies and determination of the bone oxalate content may be justified in adults to monitor oxalate burden w19x, but are clearly not justified in children. Also, measurement of plasma oxalate alone does not give adequate information about the oxalate disposal into insoluble pools such as bone. Non-invasive monitoring of the oxalate pool might have important clinical implications as it can help to define the need of transplantation procedures such as pre-emptive liver transplantation and combined liver– kidney transplantation: increasing insoluble oxalate pools would clearly indicate failure or limitations of conservative treatment and might occur even before GFR falls or plasma oxalate rises. Further longitudinal studies might help to define a set point at which deposition of oxalate into bone and other tissues increases rapidly. In the setting of a successful combined liver–kidney transplant, a reduction of BMD on the other hand could be a very useful indicator of the decrease and mobilization of insoluble oxalate pools especially from the bone; this is known to occur slowly and results in prolonged periods of hyperoxaluria despite cure of the metabolic defect w4x. We determined BMD using pQCT although evaluation by other methods such as linear absorption methods (first of all dual-energy X-ray absorptiometry (DEXA)) and ultrasound techniques is possible. With DEXA the whole skeletal oxalate content could be estimated, but this procedure is technically more difficult in children. We prefer pQCT as it allows a volumeequivalent measurement (measurement unit mgucm3) and also a separate analysis of TBD and CBD, which are impossible with DEXA and ultrasound w20x. The latter fact is rather important because TBD is regarded as a more sensitive parameter of mineral metabolism in different diagnosis and therapeutic procedures. Although the radiation exposure of pQCT and DEXA are comparable (0.1 mGy) it has to be considered that the investigation of the lumbar spine by DEXA seizes a volume that is 500–1000 times larger
BMD in children with primary hyperoxaluria type I
2239
Table 2. Blood chemistry of patients with PH 1
Serum creatinine (mgudl) BAP (mgul) Intact PTH (ngul) Serum calcium (mmolul) Serum phosphate (mmolul) Calcium-phosphate product (mmol 3 mmol)
PH 1 all (n s 10)
PH1-CT (n s 7)
PH1-ESRD (n s 3)
2.5"2.2 (0.8–7.0) 65.2"29.1 (25.8–113.5) 63.0"48.6 (13.0–159.0) 2.45"0.17 (2.18–2.59) 1.65"0.43 (1.09–2.39) 4.01"0.88 (2.73–5.21)
1.1"0.6 (0.8–2.4) 52.9"20.8 (25.8–74.5) 37.6"14.1 (13.0– 47.0) 2.5"0.1 (2.4 –2.7) 1.4"0.3 (1.1–1.6) 3.6"0.8 (3.1– 4.7)
5.8"1.5 (4.2–7.0) 89.6"33.8 (65.8–113.5) 126.5"46.0 (94.0–159.0) 2.2"0.1 (2.2–0.1) 2.2"0.2 (2.0–2.4) 4.9"0.4 (4.7–5.2)
Values are given as mean"SD (range). No significant differences between groups can be demonstrated.
than that of the distal radius measured by pQCT and runs closer to the gonads w20x. Ultrasonic methods have the advantage of being free from radiation but appear to be mostly dependent on influences by changes of bone size, structure, and tissue composition. pQCT seems to be influenced by bone size and macrostructure (e.g. cortical and trabecular area) to a minor degree compared even with DEXA, but it is also not able to detect alterations in bone structure. Despite the limitations of the individual techniques, our data show that measurement of bone density is informative in PH 1. Whether pQCT or DEXA are preferred seems less important than the continuation of bone density studies in this severe disorder. In conclusion, BMD measured by pQCT is strongly increased in children with PH 1 and ESRD and is directly correlated to plasma oxalate levels and serum creatinine. Our data indicate that measurement of BMD (by pQCT or other methods) may become a helpful diagnostic tool to detect and follow noninvasively skeletal oxalate deposition and oxalosisrelated bone changes in PH 1, especially for patients with reduced renal function, increased plasma oxalate, and after successful combined liver–kidney transplantation. Longitudinal data are necessary, however, to define the role of pQCT and bone densitometry more precisely in the management of this rare disorder. Acknowledgement. We thank Dr Gill Rumsby, University College, London, UK for performing linkage analysis and assessing hepatic AGT deficiency in eight of the reported patients.
References 1. Cochat P, Basmaison O. Current approaches to the management of primary hyperoxaluria. Arch Dis Child 2000; 82: 470–473 2. Bensman A, Legendre C, Palomera S, Thervet E, Kreis H. How to treat primary oxalosis. Nephrol Dial Transplant 1995; 11: 394–395 3. Broyer M, Jouvet P, Niaudet P, Daudon M, Revillon Y. Management of oxalosis. Kidney Int 1996; 53 wSupplx: S93–S98 4. Jamieson NV. The European Primary Hyperoxaluria Type 1 Transplant Registry report on the results of combined liveru kidney transplantation for primary hyperoxaluria 1984 –1994. Nephrol Dial Transplant 1995; 10: 33–37
5. Cochat P, Scha¨rer K. Should liver transplantation be performed before advanced renal insufficiency in primary hyperoxaluria type 1? Pediatr Nephrol 1993; 7: 212–218 6. Kemper MJ, Nolkemper D, Rogiers X et al. Preemptive liver transplantation in primary hyperoxaluria type 1: timing and preliminary results. J Nephrol 1998; 11: 46 – 48 7. Gherardi G, Poggi A, Sisca S, Calderaro V, Bonucci E. Bone oxalosis and renal osteodystrophy. Arch Pathol Lab Med 1980; 104: 105–111 8. Breed A, Chesney R, Friedman A, Gilbert E, Langer L, Lattoraca R. Oxalosis-induced bone disease: a complication of transplantation and prolonged survival in primary hyperoxaluria. J Bone Joint Surg 1981; 63: 310–316 9. Brancaccio D, Poggi A, Ciccarelli C et al. Am J Rheumatol 1981; 136: 935–939 10. Sadeghi N, DePauw L, Vienne A, Dhaene M, Struyven J, Stallenberg B. Late diagnosis of oxalosis in an adult patient: findings of bone radiography. Am J Rheumatol 1998; 170: 1248–1250 11. Mathews M, Stauffer M, Cameron EC, Maloney N, Sherrard DJ. Bone biopsy to diagnose hyperoxaluria in patients with renal failure. Ann Int Med 1979; 90: 777–779 12. Behnke B, Altrogge H, Delling G, Kruse HP, Mu¨ller-Wiefel DE. Bone mineral density in pediatric patients after renal transplantation. Clin Nephrol 1995; 46: 24–29 13. Reusz GS, Szabo A, Peter F et al. Bone metabolism and mineral density following renal transplantation. Arch Dis Child 2000; 83: 146–151 14. Behnke B, Kemper M, Kruse HP, Mu¨ller-Wiefel DE. Bone alkaline phosphatase in children with chronic renal failure. Nephrol Dial Transplant 1998; 13: 662–667 15. Reiners C, Arnold B, Brust AS, Sonnenschein W. Precision of bone mineral measurement with the new QCT scanner Stratec SCT 900. J Nucl Med 1990; 31: 856 16. Hoppe B, Kemper MJ, Bo¨kenkamp A, Portale AA, Cohn RA, Langman CB. Plasma calcium oxalate supersaturation in children with primary hyperoxaluria and end-stage renal failure. Kidney Int 1999; 56: 268–274 17. Marangella M, Cosseddu D, Petrarulo M, Vitale C, Linari F. Thresholds of serum calcium oxalate supersaturation in relation to renal function in patients with or without primary hyperoxaluria. Nephrol Dial Transplant 1993; 8: 1333–1337 18. Hoppe B, Kemper MJ, Bo¨kenkamp A, Langman CB. Plasma calcium-oxalate saturation in children with renal insufficiency and in children with renal insufficiency and primary hyperoxaluria. Kidney Int 1998; 54: 921–925 19. Marangella M, Vitale C, Petrarulo M et al. Bony content of oxalate in patients with PH or oxalosis unrelated renal failure. Kidney Int 1995; 48: 182–187 20. Scho¨nau E. Problems of bone analysis in childhood and adolescence. Pediatr Nephrol 1998; 12: 420–429
Received for publication: 13.1.01 Accepted in revised form: 7.7.01
