Skeletal Consequences of Nephropathic Cystinosis

Abstract

Nephropathic cystinosis is a rare lysosomal storage disorder. Patients present in the first year of life with renal Fanconi syndrome that evolves to progressive chronic kidney disease (CKD). Despite the multiple risk factors for bone disease, the frequency and severity of skeletal disorders in nephropathic cystinosis have not been described. We performed systematic bone and mineral evaluations of subjects with cystinosis seen at the NIH (n = 30), including history and physical examination, serum and urine biochemistries, DXA, vertebral fracture assessment, skeletal radiographs, and renal ultrasound. Additionally, histomorphometric analyses are reported on six subjects seen at the UCLA Bone and Mineral Metabolism Clinic. In NIH subjects, mean age was 20 years (range, 5 to 44 years), 60% were CKD stages G1 to G4, and 40% had a renal transplant. Mean bone mineral density (BMD) Z-scores were decreased in the femoral neck, total hip, and 1/3 radius (p < 0.05). Low bone mass at one or more sites was present in 46% of subjects. Twenty-seven percent of subjects reported one or more long bone fractures. Thirty-two percent of subjects had incidental vertebral fractures, which were unrelated to transplant status. Long-bone deformity/bowing was present in 64%; 50% had scoliosis. Diffuse osteosclerosis was present in 21% of evaluated subjects. Risk factors included CKD, phosphate wasting, hypercalciuria, secondary hyperparathyroidism, hypovitaminosis D, male hypogonadism, metabolic acidosis, and glucocorticoid/immunosuppressive therapy. Sixty-one percent of the non-transplanted subjects had ultrasonographic evidence of nephrocalcinosis or nephrolithiasis. Histomorphometric analyses showed impaired mineralization in four of six studied subjects. We conclude that skeletal deformities, decreased bone mass, and vertebral fractures are common and relevant complications of nephropathic cystinosis, even before renal transplantation. Efforts to minimize risk factors for skeletal disease include optimizing mineral metabolism and hormonal status, combined with monitoring for nephrocalcinosis/nephrolithiasis. © 2018 This article is a U.S. Government work and is in the public domain in the USA.

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy

“…Cysteamine therefore restores the efflux of cystine by reacting with it, products of the reaction being able to bypass the deficient transporter [14,15]. However, as patients receive cysteamine and as global survival improves [8], bone impairment occurring during teenage or early adulthood was recently described as a "novel" complication of cystinosis [16][17][18][19][20], further leading to the concept of "cystinosis metabolic bone disease" (CMBD) [21]. Cysteamine almost doubled the time during which patients present with a significant renal phosphate leak due to the Fanconi syndrome; even though patients receive phosphate supplementation and sometimes active vitamin D analogs, this fact may explain at least partly, the current observed bone phenotype.…”

“…Cysteamine almost doubled the time during which patients present with a significant renal phosphate leak due to the Fanconi syndrome; even though patients receive phosphate supplementation and sometimes active vitamin D analogs, this fact may explain at least partly, the current observed bone phenotype. Indeed, this concept of CMBD is currently emerging, with the description in vivo of bone fragility and symptoms [18,19], and in vitro of a functional deficit both in osteoblasts and in osteoclasts [22,23]. Even though its exact underlying pathophysiology remains unclear, at least five distinct but complementary entities can explain CMBD in addition CKD-MBD and post-transplant CKD-MBD [21]: 1) long-term consequences of hypophosphatemic rickets and renal Fanconi syndrome (i.e., hypophosphatemia, metabolic acidosis, chronic hypovolemia, hypocalcemia and 1-25 OH 2 vitamin D deficiency) together with iatrogenic effects of its supportive management, 2) deficiency in nutrition and micro-nutrition, and notably copper deficiency [24], 3) hormonal disturbances such as hypothyroidism, hypogonadism and hypoparathyroidism usually appearing in late teenage or early adulthood, and resistance to growth hormone and IGF1, 4) myopathy, and 5) intrinsic and iatrogenic bone lesions such as direct bone effects of CTNS mutation and cysteamine on osteoblasts and osteoclasts [21].…”

“…In the meantime, a North American team performed bone and mineral evaluations of 30 patients (60% undergoing conservative management and 40% after renal transplantation) with cystinosis at a mean age of 20 (range 5-44) years, including history and physical examination, biochemicals, DXA (femoral neck, 1/3 radius, total hip), vertebral fracture assessment, skeletal radiographs, and renal ultrasounds [19]. Histomorphometric data were also reported in six additional subjects from another center.…”

Management of bone disease in cystinosis: Statement from an international conference

“…Fibroblast growth factor 23 (FGF23), released by osteocytes and osteoblasts, helps maintain mineral and vitamin D homeostasis, and is the earliest detectable abnormality in bone mineral metabolism in CKD patients . However, FGF23 levels are typically normal in patients with cystinosis prior to dialysis, possibly due to hypophosphatemia …”

“…38,43 However, FGF23 levels are typically normal in patients with cystinosis prior to dialysis, possibly due to hypophosphatemia. 44 Radiographic imaging plays an important role in assessing CMBD. Although dual-energy X-ray absorptiometry (DXA) allows quantification of bone mineral density, 45 it cannot distinguish the different stages of CKD.…”