Nephropathic Cystinosis in Adults: Natural History and Effects of Oral Cysteamine Therapy

Context Nephropathic cystinosis causes the renal Fanconi syndrome in childhood. With renal replacement therapy, affected children are living longer and exhibiting previously unseen manifestations of the disease. Contribution This case series describes 100 adults age 18 to 45 years with cystinosis. Ninety-two persons received a renal allograft. Most persons had multiple complications, such as hypothyroidism, hypergonadotropic hypogonadism, pulmonary insufficiency, myopathy, retinopathy, and diabetes. One third died. A history of long-term cysteamine therapy seemed to be associated with a decreased risk for complications and death. Cautions The study was retrospective. Data were from selected patients attending a national referral center. Implication Nephropathic cystinosis is a multisystemic disease that may be mitigated by cysteamine therapy. The Editors Nephropathic cystinosis, the most common identifiable cause of the renal Fanconi syndrome in childhood, is an autosomal recessive storage disease caused by defective transport of cystine out of lysosomes (13). The renal tubular damage of cystinosis, which begins at 6 to 12 months of age, is associated with polyuria, polydipsia, dehydration, acidosis, hypophosphatemic rickets, hypokalemia, hypocalcemic tetany, hypocarnitinemia, and growth retardation. These disorders are treated with nutritional replacements and, sometimes, growth hormone therapy. Renal glomerular damage generally becomes apparent by 2 to 5 years of age and results in end-stage renal disease by 9 to 10 years of age unless cystine-depleting therapy is initiated early in life (13). Renal replacement therapy has transformed cystinosis from an exclusively pediatric disease to one that affects individuals up to (and potentially beyond) 50 years of age. Nonrenal complications of nephropathic cystinosis were initially thought to be limited to photophobia and hypothyroidism. Once kidney transplantation allowed survival past 10 years of age, the multisystemic nature of cystinosis became apparent (4). Complications include retinal blindness (5), vacuolar myopathy (6, 7), swallowing dysfunction (8, 9), diabetes mellitus (10), pancreatic exocrine insufficiency (11), central nervous system involvement (12, 13), pulmonary dysfunction (14), male hypogonadism (15), benign intracranial hypertension (16), vascular calcifications (17), and nodular regenerating hyperplasia of the liver (18). The basic defect in cystinosis was elucidated in 1982 (1, 2), and the causative gene, CTNS (OMIM 606272), was discovered in 1998 (19). CTNS is located on chromosome 17p (20) and encodes cystinosin, a 367amino acid protein with 7 transmembrane domains (19). Cystinosin transports the disulfide amino acid cystine out of lysosomes and into the cytoplasm of cells, where it is reduced to cysteine. This transport process is defective in cystinosis (2123), causing intralysosomal accumulation and, in most cells, crystal formation (Figure 1). This pathologic process is attenuated in some variants of cystinosis with residual transport activity (24). Specifically, onset of renal disease in adolescence indicates intermediate cystinosis (2, 25), and photophobia due to corneal crystals is the only symptom of ocular cystinosis (also called nonnephropathic cystinosis) (2, 26). Figure 1. Clinical findings in adults with nephropathic cystinosis not treated with oral cysteamine. A. B. C. Targeted therapy for nephropathic cystinosis involves oral administration of the free aminothiol cysteamine (27). This membrane-permeable compound enters lysosomes, where it participates with cystine in a disulfide interchange reaction, forming cysteine and cysteinecysteamine mixed disulfide (28), both of which can exit the cystinotic lysosome by using transporters other than the defective cystinosin (29). Oral cysteamine (Cystagon, Mylan Pharmaceuticals, Morgantown, West Virginia), which was approved by the U.S. Food and Drug Administration in 1994, is given every 6 hours at a dosage of 60 to 90 mg/kg of body weight per day (1.3 to 1.95 g/m2 of height per day). When adherence is consistent, this therapy achieves leukocyte cystine depletion of up to 95% and reduces the cystine content of parenchymal tissues, such as the muscle and liver (30). Oral cysteamine therapy preserves renal glomerular function, enhances growth, and obviates the need for l-thyroxine replacement therapy (3133). It also prevents the development of swallowing difficulties (9), coronary artery calcifications (17), and damage to the posterior segment of the eye (34). In addition, topical cysteamine eye drops dissolve the corneal crystals of cystinosis (3537). We present the clinical characteristics of 100 adults with nephropathic cystinosis who were examined at the National Institutes of Health (NIH) Clinical Center between 1985 and 2006. Untreated cystinosis is a devastating disease, with a 33% mortality rate and nearly universal morbidity in adults. Long-term oral cysteamine administration has substantial beneficial effects on survival and final height and weight and helps prevent diabetes mellitus, myopathy, pulmonary dysfunction, and hypercholesterolemia, which are associated with nephropathic cystinosis. Methods Patients All patients were enrolled in NIH Clinical Center protocol 78-HG-0093, Use of Cysteamine in the Treatment of Cystinosis, and gave written informed consent to participate. The protocol was approved by the National Human Genome Research Institute Institutional Review Board and is consistent with the principles of the Declaration of Helsinki. Patients seen only for ophthalmic evaluation and those with intermediate or ocular cystinosis were excluded. Otherwise, every patient with classic nephropathic cystinosis who was admitted to the NIH Clinical Center between January 1985 and May 2006 and was at least 18 years of age at admission was included. Data from each patient's latest admission were examined. This process resulted in analysis of data from 100 consecutive patients, of whom 35 were described in 1993 (38). Twenty-four of the 35 patients have since had follow-up admissions. The diagnosis of nephropathic cystinosis was based on a typical history, the presence of corneal crystals, and an off-treatment polymorphonuclear leukocyte cystine level greater than 3 nmol half-cystine/mg protein (normal value, <0.2 nmol half-cystine/mg protein; range in cystinosis, 3 to 25 nmol half-cystine/mg protein) (13). Cystine depletion was considered adequate if the leukocyte cystine level was less than 2.5 nmol half-cystine/mg protein 5 to 6 hours after a dose of oral cysteamine. Cystine was measured by using the cystine binding protein assay (39). Adherence to therapy was assessed independent of evaluation of complications of cystinosis. Criteria for Diagnosis of Complications Hypothyroidism was always treated in our patients with cystinosis and was diagnosed if a patient was receiving l-thyroxine replacement therapy. Hypogonadism was diagnosed if a male patient was receiving testosterone replacement, had a low serum testosterone level, or had a follicle-stimulating hormone concentration greater than 30 U/L (normal range, 1 to 12 U/L). Sexual development was evaluated by using the stages of Marshall and Tanner (40, 41), ranging from prepubertal (stage I) to fully developed (stage V). Patients were considered to have pulmonary dysfunction if their mean FVC, FEV1, total lung capacity (TLC), and diffusing capacity for carbon monoxide (DLco) values were less than 80% of predicted values. Swallowing abnormalities were diagnosed on the basis of a detailed examination showing at least mild impairment according to the published Swallowing Severity Score and Oral Muscle Composite Score (9). Myopathy was defined clinically by wasting of the distal muscles of the hand. Hypercholesterolemia was defined as a total serum cholesterol greater than 5.2 mmol/L (>200 mg/dL) or current receipt of a statin drug to treat hypercholesterolemia. Retinopathy was defined by clinical examination, legal blindness in at least 1 eye, or an abnormal electroretinogram. Vascular and cerebral calcifications were identified by computed tomography of the chest and brain, respectively. Diabetes mellitus was diagnosed if patients required insulin therapy. Molecular Diagnostic Techniques Mutation analysis of the CTNS gene was done by using a multiplex method to detect the 57-kb deletion, which is present in approximately 50% of North American patients (4244). Role of the Funding Source The study received no external funding. Results General Characteristics One hundred patients age 18 to 45 years (mean age, 26.2 years [SD, 6.5]) who had cystinosis met our criteria for analysis. The male-to-female ratio was 58:42. Of the 44 patients who were evaluated for sexual development, 1 was Tanner stage I, 2 were stage II, 6 were stage III, 21 were stage IV, and 14 were stage V. Three women each delivered 1 healthy child. The leukocyte cystine level while not receiving cysteamine therapy was available for 32 patients; the mean value was 8.3 nmol half-cystine/mg protein (SD, 3.6). Kidney Transplantation Most patients (92%) had received a renal allograft (Table 1), and many received more than 1. For all 92 patients who received a transplant, the first allograft was done at a mean age of 12.3 years (SD, 4.2). Of the 92 initial allografts, 42 were from living donors and 42 were from cadavers; for 8 allografts, the donor was not specified. Forty-four patients received a second renal transplant (13 from living donors, 29 from cadavers, and 2 from an unspecified source), and 6 patients received a third renal transplant (3 from living donors and 3 from cadavers). Seven of the 8 patients with native kidneys were 18 to 21 years of age, and 1 was 27 years of age. Table 1. Patient Characteristics Of the 92 patients who underwent transplantation, 17 were uremic at the time of their most recent NIH admission. Laboratory data, which were available for 74