Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Renal Transplantation
You have accessRestricted Access

Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation

Masako Ueda, Kevin O’Brien, Douglas R. Rosing, Alexander Ling, Robert Kleta, Dorothea McAreavey, Isa Bernardini and William A. Gahl
CJASN May 2006, 1 (3) 555-562; DOI: https://doi.org/10.2215/CJN.01431005
Masako Ueda
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin O’Brien
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Douglas R. Rosing
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexander Ling
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert Kleta
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dorothea McAreavey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Isa Bernardini
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William A. Gahl
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

Cystinosis, an autosomal recessive disorder of lysosomal cystine accumulation, results from mutations in the CTNS gene that encodes the lysosomal cystine transporter, cystinosin. Renal tubular Fanconi syndrome occurs in infancy, followed by rickets, growth retardation, photophobia, and renal failure, which requires renal transplantation at approximately 10 yr of age. Treatment with cysteamine decreases cellular cystine levels, retards renal deterioration, and allows for normal growth. Patients with a history of inadequate cystine depletion therapy may survive, after renal transplantation, into the third to fifth decades but will experience other, extrarenal complications of the disease. Routine chest and head computed tomography scans of 41 posttransplantation patients with cystinosis were reviewed for vascular calcification. The radiologic procedures had been performed to examine lung and brain parenchyma, so there was little ascertainment bias. Thirteen of the 41 patients had vascular calcification, including 11 with coronary artery calcification. One 25-yr-old man required three-vessel coronary artery bypass graft surgery. There were no significant differences between the 13 patients with calcification and the 28 without calcification in the following parameters: Time on dialysis, frequency of transplantation, hypertension, hypercholesterolemia, homozygosity for the 57-kb deletion in CTNS, serum creatinine, and calcium-phosphate product. However, the finding of vascular calcification correlated directly with duration of life without cysteamine therapy and inversely with duration of life under good cystine-depleting therapy. The accumulation of intracellular cystine itself maybe a risk factor for vascular calcifications, and older patients with cystinosis should be screened for this complication.

Cystinosis is an autosomal recessive lysosomal storage disease with an estimated incidence of one in 100,000 to 200,000 live births (1,2). CTNS, the gene that is responsible for cystinosis, maps to chromosome 17p13 (3) and encodes a lysosomal membrane transport protein named cystinosin (4). Approximately half of patients who have cystinosis and are of northern European descent carry at least one allele that bears a specific 57-kb deletion that encompasses the CTNS gene (4,5). For all patients with nephropathic cystinosis, a defect in cystinosin dramatically diminishes egress of cystine from lysosomes (6,7), resulting in intralysosomal cystine accumulation and crystal formation in most organ systems (1,2). Infants with cystinosis are normal at birth but develop renal tubular Fanconi syndrome at 6 to 12 mo of age and renal failure at approximately 10 yr of age (8). In addition, hypothyroidism (1,2), myopathy (9,10), swallowing dysfunction (11), diabetes (12), male hypogonadism (13), pulmonary dysfunction (14), and central nervous system involvement (15–17) complicate this disorder in adolescence and early adulthood (18).

The therapy of nephropathic cystinosis includes replacement of the mineral and electrolyte losses associated with the renal tubular Fanconi syndrome. When glomerular failure supervenes, dialysis or kidney transplantation is required. In addition, specific therapy directed at intracellular cystine depletion involves administration of oral cysteamine bitartrate, or Cystagon (Mylan Pharmaceuticals, Morgantown, WV) (19). Chronic use of oral cysteamine, now accepted as the treatment of choice for cystinosis throughout the world, retards renal glomerular deterioration (20,21), enhances growth, and obviates the need for l-thyroxine replacement in patients with cystinosis (22). Cysteamine hydrochloride eyedrops also dissolve the corneal crystals of cystinosis (23,24).

Increasing numbers of individuals with cystinosis are receiving renal transplants and living into adulthood, and more late complications of the disease and its treatments are being recognized. As part of our comprehensive evaluations of adult patients with cystinosis after renal transplantation, we performed head and chest computed tomography (CT) studies, which revealed calcification in various vessels, most notable the coronary arteries. We now present these findings as a complication of nephropathic cystinosis after renal transplantation in patients with a history of inadequate oral cysteamine therapy.

Materials and Methods

Patients

Nephropathic cystinosis was diagnosed on the basis of characteristic clinical findings plus an elevated leukocyte cystine content: >3.0 nmol half-cystine/mg protein (normal <0.2). All patients were enrolled in a protocol that was approved by the Institutional Review Boards of the National Institute of Child Health and Human Development and the National Human Genome Research Institute, and all patients gave written informed consent. Cystinosis severity scores (5) were based on age at diagnosis, the Fanconi Syndrome Index (a measure of aminoaciduria [25]), pretreatment leukocyte cystine levels (measured using the cystine binding protein assay [26]), age at renal failure, and age at which serious extrarenal complications occurred (27).

Radiologic Procedures

All of the CT studies were obtained according to standard clinical protocols for the head and the body. For the brain studies, the earliest two were obtained on spiral CT equipment (General Electric Medical Systems, Milwaukee, WI). All subsequent brain studies were conducted using multichannel (“multislice”) machines (Philips Medical Systems, Eindhoven, Netherlands; and General Electric Medical Systems). All studies used 5-mm or thinner collimation. For the torso studies, the earliest three were performed on spiral CT equipment, using either 5- or 10-mm collimation and 1:1 pitch; all subsequent chest studies were obtained using these same multichannel scanners and consecutive 5-mm images. Both head and chest studies were conducted without vascular contrast administration.

Molecular Diagnostics

Mutation analysis of the CTNS gene, using multiplex analysis of the 57-kb deletion, was performed as described (5,28).

Results

Between October 1997 and January 2005, 41 patients who were aged 8 to 47 and had nephropathic cystinosis underwent a CT scan of the chest to rule out parenchymal lung disease. When multiple CT scans were available on a patient, only the most recent result was included in this analysis. Thirteen (32%) patients had vascular calcification detected incidentally; in 11, the calcification was in the coronary arteries. The characteristics of the 13 patients with calcifications were compared with those of 28 patients who lacked vascular calcifications (Table 1). The 13 patients with vascular calcifications were older (P = 1 × 10−7) and had lived longer without cysteamine therapy than the 28 patients who lacked vascular calcifications (P = 3 × 10−6). The duration of treatment with oral cysteamine therapy was shorter for the group with vascular calcifications than for the group without this complication, although the difference did not approach statistical significance (P = 0.21). When all 41 patients were considered, the fraction with vascular calcifications increased with the number of years off cysteamine (Figure 1A) and decreased with the number of years on cysteamine (Figure 1B). The groups with and without vascular calcifications differed significantly in the frequency of diabetes (P = 0.0034); all of the patients who required insulin had undergone a renal allograft procedure, were receiving prednisone, and had their diabetes for between 4 and 11 yr at the time of the CT examination. The groups with and without calcifications did not differ significantly in the duration of dialysis (P = 0.06) or in the fraction of patients who had received a renal allograft (P = 0.07). The two groups resembled each other in the frequency of hypertension, hypercholesterolemia, and homozygosity for the 57-kb deletion in CTNS (Table 1). They did not differ in mean serum creatinine concentration or calcium-phosphate product (Table 1). The posttransplantation patients took a wide variety of immunosuppressive agents but did not commonly receive lipid-lowering agents.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Percentage of patients who had cystinosis and vascular calcifications, divided according to the number of years off oral cysteamine therapy (A) or on cysteamine therapy (B).

View this table:
  • View inline
  • View popup
Table 1.

Characteristics of patients who had cystinosis with and without vascular calcifications

The clinical characteristics of the patients with vascular calcification are shown in Table 2. Twenty-three renal allografts had been performed on the 13 patients, nine of whom had undergone dialysis before the procedure. In addition to the three patients with total cholesterol levels >200 mg/dl (Tables 1 and 2), three other patients had triglyceride levels >150 mg/dl and one patient with diabetes had an LDL cholesterol level >100 mg/dl. All of these values constitute cardiovascular disease risk factors according to the National Cholesterol Education Program Adult Treatment Plan III guidelines.

View this table:
  • View inline
  • View popup
Table 2.

Clinical features of patients with cystinosis and radiographic evidence of vascular calcificationsa

Overall, the calcification involved various vessels, including the aorta, coronary, left subclavian, right brachiocephalic, carotid, and vertebral arteries. For example, extensive vertebral artery calcification was visible on CT scan of the head in patient 6 (Figure 2). The following cases illustrate the potential end-organ ischemic complications that can occur in posttransplantation patients with cystinosis and vascular calcification.

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Vertebral artery calcifications on coronal computed tomography (CT) slice of patient 6. The black arrows highlight dense calcification of the vertebral arteries in this 33-yr-old man.

Patient 2 (Table 2) was a 25-yr-old Hispanic man who presented with symptoms of exercise-induced angina. He was born after an uncomplicated pregnancy but developed failure to thrive at 6 mo of age. At 1 yr of age, renal Fanconi syndrome and rickets were diagnosed. A definitive diagnosis of cystinosis was not made until 5 yr of age. The patient began hemodialysis at 7.5 yr of age and within 6 mo received a cadaveric renal allograft. He developed hypertension at age 10, hypothyroidism 1 yr later, and hypercholesterolemia during adolescence. Chronic graft rejection required a second, living-related donor transplant at 20 yr of age.

This patient’s severity score was 2.7, reflecting a significant degree of impairment as a result of nephropathic cystinosis (5). His leukocyte cystine level, without cystine-depleting therapy, was 10.8 nmol half-cystine/mg protein (normal <0.2). Cysteamine therapy, in the form of phosphocysteamine, was initiated upon the patient’s first admission to the National Institutes of Health (NIH) Clinical Center at 11 yr of age. Later, cysteamine bitartrate (Cystagon) was administered. The patient received cysteamine therapy between the ages of 10 and 15 yr, during which time his leukocyte cystine level averaged 2.2 nmol half-cystine/mg protein (n = 8; range 0.6 to 4.9) on doses ranging from 275 to 400 mg every 6 h. During this time, the leukocyte cystine was >2.5 nmol half-cystine/mg protein for a full year, meaning that compliant therapy was achieved for a total of 4 yr (Table 2). The patient did not return to the NIH for 10 yr, at which time he was 25 yr of age.

Recently, the patient complained of a “pressure-like” sensation while walking briskly or climbing stairs. He denied nausea, dyspnea, or radiation of the pressure or pain. He had never smoked. Further evaluation revealed hypothyroidism with a thyroid-stimulating hormone of 414 μIU/ml (normal 0.40 to 4.00); free T4 of 0.2 ng/dl (normal 0.7 to 1.8); and dyslipidemia with a total serum cholesterol of 233 mg/dl (normal 100 to 200 mg/dl), LDL of 163 mg/dl (normal 65 to 129), HDL of 37 mg/dl, and triglycerides of 200 mg/dl (normal <150). The hemoglobin was 8.6 g/dl (normal 12.7 to 16.7), and the hematocrit was 25.2% (normal 36.7 to 48.3%), with a mean corpuscular volume of 91 fL (normal 79 to 98).

The resting 12-lead electrocardiogram showed marked sinus bradycardia with low voltage and nonspecific ST segment and T-wave abnormalities. A resting echocardiogram revealed no regional wall motion abnormalities or cardiomegaly. A routine chest CT, obtained as part of our pulmonary evaluation, showed marked calcification in the coronary arteries (Figure 3).

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Chest CT of patient 2. (A and B) Dense calcification in the left anterior descending artery. (C) Calcification in the proximal portion of the right coronary artery (upper left side of heart) and the left main artery (lower right side of heart). (D) Calcification in the circumflex artery.

The patient underwent a combination dipyridamole and modified Bruce protocol treadmill stress test with thallium scintigraphy. The treadmill test was stopped after 4 min, 7 s (2.7 metabolic equivalents), because the patient complained of retrosternal chest pain and pressure, dyspnea, and pain radiating into his left arm. At peak exercise, the electrocardiogram showed 2-mm ST segment depression that resolved with rest. Thallium scintigraphy revealed a reversible perfusion defect in the inferior, apical, and septal segments of the myocardium. Subsequent cardiac catheterization (Figure 4) revealed several high-grade stenoses in the proximal left anterior descending artery, a 70% stenosis of the left circumflex before the first obtuse marginal branch, and 80% stenosis in the first obtuse marginal branch. There was also an almost 100% stenosis of the middle portion of the right coronary artery with left to right collaterals (data not shown). Coronary artery bypass was performed using both internal mammary arteries and one saphenous vein graft. Renal function remained stable throughout the hospitalization, with a creatinine clearance of 35 ml/min per 1.73 m2. The patient was started on a β blocker, a statin, and low-dose aspirin and was discharged with follow-up care.

Figure 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4.

Coronary angiogram of patient 2. The large black arrows highlight high-grade occlusions in the proximal portion of the left circumflex and the obtuse marginal branch of the circumflex artery. The small black arrows highlight high-grade occlusions in the left anterior descending branch.

Patient 8 was a 37-yr-old white man with a history of three renal transplants and inadequate cysteamine treatment. He received a diagnosis of nephropathic cystinosis at age 13 mo and hypothyroidism at age 4 yr. Progressive chronic renal failure required hemodialysis and peritoneal dialysis for approximately 6 mo, followed by his first renal transplant at age 14. He received two additional renal allografts at ages 25 and 32 yr, after chronic graft rejection.

This patient had a cystinosis severity score of 1.8. He was homozygous for the 57-kb deletion in CTNS. The patient did not begin oral cysteamine therapy until age 20, and he tolerated 300 to 450 mg either three or four times per day over the next 17 yr. Leukocyte cystine levels from age 20 to 29 yr averaged 1.4 nmol half-cystine/mg protein (n = 9; range 0.5 to 2.7), but the patient did not return to the NIH between 29 and 37 yr of age. Hence, this patient is credited with 9 yr of “adequate” cysteamine therapy (Table 2).

The patient was hospitalized for a left-sided ischemic stroke at age 36. During that admission, he developed congestive heart failure as a result of volume overload and complained of substernal chest pain. Cardiac catheterization revealed a 75% lesion in his right coronary artery and a 40% lesion in the mid-left anterior descending coronary artery. The right coronary lesion was not amenable to percutaneous intervention, so medical management was initiated.

On routine admission to the NIH Clinical Center at age 37, the patient denied exertional chest pain or anginal equivalents with his usual activities. His BP was mildly elevated despite therapy with a β blocker, diuretic, and an angiotensin-converting enzyme inhibitor. He had a residual right homonymous hemianopsia and mild memory impairment from his recent cerebrovascular accident. A resting echocardiogram estimated his ejection fraction at 49% with mild global left ventricular hypokinesis. His serum creatinine was 2.6 mg/dl. Despite cholesterol-lowering therapy, his total cholesterol was 168 mg/dl, the HDL cholesterol was 39 mg/dl, the LDL cholesterol was 80 mg/dl, and the triglycerides were 313 mg/dl. The total homocysteine was 17 μM (range 0 to 13), and the high-sensitivity C-reactive protein was 0.673 mg/dl (normal <0.8). The cysteamine dosage regimen was 300 mg every 6 h, and his leukocyte cystine level was 2.6 nmol half-cystine/mg protein.

High resolution CT revealed evidence of several vascular calcifications, including bilateral calcification in the cavernous portions of the internal carotid arteries (Figure 5). The chest and abdominal CT showed calcification in the right and left coronary arteries, within the aortic arch, and in the distal portion of the abdominal aorta.

Figure 5.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5.

Calcifications on a coronal CT slice in the internal carotid arteries of patient 8. The black arrows point to calcification in the cavernous portion of the carotid arteries in this 37-yr-old man.

Bicycle stress echocardiography revealed reversible myocardial ischemia. The test was stopped after only 5 min because of leg pain and shortness of breath. At peak exercise, 1-mm horizontal ST segment depression occurred in leads III and AVF, 1.5-mm horizontal depression occurred in leads II and V6, and 4-mm horizontal depression occurred in leads V4 and V5. The changes returned to baseline after 9 min of recovery. The echocardiogram demonstrated akinesis of the apex and hypokinesis of the mid-anterior and mid-lateral walls. The final impression was anterolateral ischemia and likely multivessel coronary artery disease. The decision was made first to institute more aggressive medical management for coronary artery disease and then to have the patient evaluated for bypass surgery by his medical team at home.

Discussion

The destruction of individual parenchymal cells, perhaps through enhanced activation of apoptotic mechanisms (29), is considered the basis for tissue injury in nephropathic cystinosis. This process affects the kidney very early; the thyroid gland in late childhood; and the pancreas, muscle, and central nervous system in early adulthood (1,2). Most likely, the full spectrum of extrarenal involvement in cystinosis has not yet been elucidated; many of the late complications of cystinosis were recognized only after renal transplantation allowed patients to survive past adolescence (27).

We now add arteriopathy to the list of late complications of poorly treated cystinosis. The frequency of this finding can only be estimated, but in our cohort, 13 of 41 individuals displayed calcification of various medium and large vessels, most notable the coronary arteries and the arteries that feed the circle of Willis. Our patients underwent routine CT scans of the head and chest and were not selected on the basis of signs of vascular or cardiac compromise.

The high prevalence of cardiovascular morbidity and mortality in patients with renal disease has been well documented (30–33), and our patients had several risk factors for vascular calcification and obstructive atherosclerosis. All 13 such patients in our cohort had endured renal failure and had undergone at least one renal allograft procedure. This frequency of renal transplantation (100%) was slightly greater than the frequency among patients who lacked calcifications (79%), but renal transplantation actually reduces the frequency of coronary artery calcification in patients with renal failure (34).

Nine of 13 patients with vascular calcifications had undergone previous dialysis. However, time on dialysis in this group did not differ significantly from that of the patients who had cystinosis and did not have vascular calcifications (Table 1).

Diabetes is another a major risk factor for atherosclerosis and coronary artery disease, and six (46%) of our 13 patients with vascular calcifications had diabetes (Table 1). This was significantly greater than the frequency of diabetes (2 of 28; 7%) in patients without calcifications and probably reflects the older age of the patients with calcifications; insulin dependence began at a mean age of 26 yr in our patients. Immunosuppressive agents such as tacrolimus and steroids also may have contributed to glucose intolerance among our posttransplantation patients (35–38).

Three of our 13 patients with vascular calcifications had total serum cholesterol levels >200 mg/dl, but this did not differ from the frequency for patients who did not have vascular calcifications (Table 1). Patients with posttransplantation cystinosis are known to exhibit elevations in total serum cholesterol (27).

Another possible risk factor for vascular calcifications in cystinosis involves abnormalities of calcium and phosphate homeostasis. Pretransplantation patients with cystinosis may develop medullary nephrocalcinosis (39), related to their urinary phosphate and calcium loads, which are substantially increased as a result of renal tubular Fanconi syndrome and the use of supplemental vitamin D to treat this complication. Ectopic calcification can occur in the basal ganglia and periventricular areas of the brain in posttransplantation patients who have cystinosis and have not received long-term cysteamine therapy (16). However, serum calcium and phosphate levels in our patients with vascular calcification were not elevated. Moreover, the calcium-phosphate product, which strongly correlates with osteoblastic activity of vascular cells (40,41) and with the prevalence of vascular calcification (31–33), was not elevated in our patients. In fact, the average calcium-phosphate product was 38 mg2/dl2 (Table 1), similar to that of our patients without vascular calcifications (41 mg2/dl2) and significantly lower than the average of 65 mg2/dl2 found in patients with coronary artery calcification and ESRD (32).

We could not attribute vascular calcification to hypertension, because our 13 posttransplantation patients with calcifications had the same frequency of hypertension (Table 1) as the 28 patients who lacked vascular calcifications. Other risk factors, such as hyperhomocysteinemia, increased C-reactive protein or advanced glycation end products, and markers of inflammation, could not be assessed because this was a retrospective analysis.

Outside of the moderately increased risk associated with diabetes, no specific risk factor or combination of risk factors for the development of vascular calcifications could be identified within our cohort of patients with cystinosis. Consequently, we propose that cystinosis itself is a risk factor for the development of vascular calcifications. Cystine continues to accumulate with age in cystinosis, and our affected patients were significantly older than their counterparts without vascular calcifications (Table 1). Moreover, the frequency of vascular calcifications was higher in patients who had been off cysteamine treatment for longer (Figure 1A) and was lower in patients who had been on cysteamine therapy longer (Figure 1B). Mechanistically, cysteamine lowers intracellular cystine stores, which may destroy individual vascular endothelial cells, resulting in secondary calcification. Cysteamine treatment has no known effect on the other putative risk factors for vascular calcifications.

Patients who have cystinosis and a history of chronic renal failure that necessitates dialysis and renal replacement therapy should be considered at high risk for the development of vascular calcifications and atherosclerosis. Beginning in early adulthood, these patients require careful monitoring and aggressive treatment to prevent the development of organ ischemia related to vascular calcification. Sustained oral cysteamine therapy should be provided to patients of all ages who have cystinosis to prevent the cellular destruction that results in tissue deterioration.

Acknowledgments

This work was supported in part by the Intramural Research Programs of the National Institutes of Health, specifically, those of the National Human Genome Research Institute and the Hatfield Clinical Research Center.

We thank Brad Tinloy for statistical consultation.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Received October 23, 2005.
  • Accepted January 3, 2006.
  • Copyright © 2006 by the American Society of Nephrology

References

  1. ↵
    Gahl WA, Thoene JG, Schneider JA: Cystinosis: A disorder of lysosomal membrane transport. In: The Metabolic and Molecular Bases of Inherited Disease, 8th Ed., edited by Scriver CR, Beaudet AL, Valle D, Sly WS, New York, McGraw-Hill,2001 , pp5085– 5108
  2. ↵
    Gahl WA, Thoene JG, Schneider JA: Cystinosis. N Engl J Med347 :111– 121,2002
    OpenUrlCrossRefPubMed
  3. ↵
    The Cystinosis Collaborative Research Group: Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. Nat Genet10 :246– 248,1995
    OpenUrlCrossRefPubMed
  4. ↵
    Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore SA, Callen DF, Gribouval O, Broyer M, Bates GP, van’T Hoff W, Antignac C: A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet18 :319– 324,1998
    OpenUrlCrossRefPubMed
  5. ↵
    Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA: CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet63 :1352– 1362,1998
    OpenUrlCrossRefPubMed
  6. ↵
    Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD: Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis. Science217 :1263– 1265,1982
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Gahl WA, Tietze F, Bashan N, Steinherz R, Schulman JD: Defective cystine exodus from isolated lysosome-rich fractions of cystinotic leukocytes. J Biol Chem257 :9570– 9575,1982
    OpenUrlFREE Full Text
  8. ↵
    Gretz N, Manz F, Augustin R, Barrat TM, Bender-Gotze C, Brandis M, Bremer HJ, Brodehl J, Broyer M, Bulla M, Callis L, Chantler C, Diekmann L, Dillon MJ, Egli F, Ehrich JH, Endres W, Fanconi A, Feldhoff C, Geisert J, Gekle D, Gescholl-Bauer B, Grote K, Gruttner R, Hagge W, Haycock CB, Hennemann H, Klare B, Leupold D, Lohr H, Michalk D, Oliveira A, Ott F, Pistor K, Rau J, Scharer K, Schindera F, Schmidt H, Schulte-Wissermann H, Verrier-Jones K, Weber HP, Willenbockel U, Wolf H: Survival time in cystinosis: A collaborative study. Proc Eur Dial Transplant Assoc19 :582– 589,1983
    OpenUrlPubMed
  9. ↵
    Gahl WA, Dalakas MC, Charnas L, Chen KT, Pezeshkpour GH, Kuwabara T, Davis SL, Chesney RW, Fink J, Hutchison HT: Myopathy and cystine storage in muscles in patients with nephropathic cystinosis. N Engl J Med319 :1461– 1464,1988
    OpenUrlPubMed
  10. ↵
    Charnas LR, Luciano CA, Dalakas M, Gilliant RW, Bernardini I, Cwik VA, Fraker D, Brushart TA, Gahl WA: Distal vacuolar myopathy in nephropathic cystinosis. Ann Neurol35 :181– 188,1994
    OpenUrlCrossRefPubMed
  11. ↵
    Sonies BC, Ekman EF, Andersson HC, Adamson MD, Kaler SG, Markello TC, Gahl WA: Swallowing dysfunction in nephropathic cystinosis. N Engl J Med323 :565– 570,1990
    OpenUrlPubMed
  12. ↵
    Fivush B, Green OC, Porter CC, Balfe JW, O’Regan S, Gahl WA: Pancreatic endocrine insufficiency in posttransplant cystinosis. Am J Dis Child141 :1087– 1089,1987
    OpenUrlCrossRefPubMed
  13. ↵
    Chik CL, Friedman A, Merriam GR, Gahl WA: Pituitary-testicular function in nephropathic cystinosis. Ann Intern Med119 :568– 575,1993
    OpenUrlPubMed
  14. ↵
    Anikster Y, Lacbawan F, Brantly M, Gochuico BL, Avila NA, Travis W, Gahl WA: Pulmonary dysfunction in adults with nephropathic cystinosis. Chest119 :394– 401,2001
    OpenUrlCrossRefPubMed
  15. ↵
    Ehrich JH, Stoeppler L, Offner G, Brodehl J: Evidence for cerebral involvement in nephropathic cystinosis. Neuropaediatrie10 :128– 137,1979
    OpenUrlCrossRef
  16. ↵
    Fink JK, Brouwers P, Barton N, Malekzadeh MH, Sato S, Hill S, Cohen WE, Fivush B, Gahl WA: Neurologic complications in long-standing nephropathic cystinosis. Arch Neurol46 :543– 548,1989
    OpenUrlCrossRefPubMed
  17. ↵
    Theodoropoulos DS, Krasnewich D, Kaiser-Kupfer MI, Gahl WA: Classic nephropathic cystinosis as an adult disease. JAMA270 :2200– 2204,1993
    OpenUrlCrossRefPubMed
  18. ↵
    Broyer M, Tete MJ, Guest G, Bertheleme JP, Labrousse F, Poisson M: Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine. J Inherit Metab Dis19 :65– 75,1996
    OpenUrlCrossRefPubMed
  19. ↵
    Thoene JG, Oshima RG, Crawhall JC, Olson DL, Schneider JA: Cystinosis. Intracellular cystine depletion by aminothiols in vitro and vivo. J Clin Invest58 :180– 189,1976
    OpenUrlCrossRefPubMed
  20. ↵
    Gahl WA, Reed GF, Thoene JG, Schulman JD, Rizzo WB, Jonas AJ, Denman DW, Schlesselman JJ, Corden BJ, Schneider JA: Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med316 :971– 977,1987
    OpenUrlCrossRefPubMed
  21. ↵
    Markello TC, Bernardini IM, Gahl WA: Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med328 :1157– 1162,1993
    OpenUrlCrossRefPubMed
  22. ↵
    Kimonis VE, Troendle J, Rose SR, Yang ML, Markello TC, Gahl WA: Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis. J Clin Endocrinol Metab80 :3257– 3261,1995
    OpenUrlCrossRefPubMed
  23. ↵
    Kaiser-Kupfer MI, Fujikawa L, Kuwabara T, Jain S, Gahl WA: Removal of corneal crystals by topical cysteamine in nephropathic cystinosis. N Engl J Med316 :775– 779,1987
    OpenUrlPubMed
  24. ↵
    Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaiser-Kupfer MI: Corneal crystals in nephropathic cystinosis: Natural history and treatment with cysteamine eyedrops. Mol Genet Metab71 :100– 120,2000
    OpenUrlCrossRefPubMed
  25. ↵
    Charnas LR, Bernardini I, Rader D, Hoeg JM, Gahl WA: Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med324 :1318– 1325,1991
    OpenUrlCrossRefPubMed
  26. ↵
    Oshima RG, Willis RC, Furlong CE, Schneider JA: Binding assays for amino acids. The utilization of a cystine binding protein from Escherichia coli for the determination of acid-soluble cystine in small physiological samples. J Biol Chem249 :6033– 6039,1974
    OpenUrl
  27. ↵
    Gahl WA, Kaiser-Kupfer MI: Complications of nephropathic cystinosis after renal failure. Pediatr Nephrol1 :260– 268,1987
    OpenUrlCrossRefPubMed
  28. ↵
    Kleta R, Anikster Y, Lucero C, Shotelersuk V, Huizing M, Bernardini I, Park M, Thoene J, Schneider J, Gahl WA: CTNS mutations in African American patients with cystinosis. Mol Genet Metab74 :332– 337,2001
    OpenUrlCrossRefPubMed
  29. ↵
    Park M, Helip-Wooley A, Thoene J: Lysosomal cystine storage augments apoptosis in cultured human fibroblasts and renal tubular epithelial cells. J Am Soc Nephrol13 :2878– 2887,2002
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Goldsmith DJ, Covic A: Coronary artery disease in uremia: Etiology, diagnosis, and therapy. Kidney Int60 :2059– 2078,2001
    OpenUrlCrossRefPubMed
  31. ↵
    Prichard S: Risk factors for coronary artery disease in patients with renal failure. Am J Med Sci325 :209– 213,2003
    OpenUrlCrossRefPubMed
  32. ↵
    Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med342 :1478– 1483,2000
    OpenUrlCrossRefPubMed
  33. ↵
    Querfeld U: The clinical significance of vascular calcification in young patients with end-stage renal disease. Pediatr Nephrol19 :478– 484,2004
    OpenUrlCrossRefPubMed
  34. ↵
    Meier-Kriesche H-U, Schold JD, Srinivas TR, Reed A, Kaplan B: Kidney transplantation halts cardiovascular disease progression in patients with end-stage renal disease. Am J Transplant4 :1662– 1669,2004
    OpenUrlCrossRefPubMed
  35. ↵
    Sasso FC, Carbonara O, Nasti R, Campana B, Marfella R, Torella M, Nappi G, Torella R, Cozzolino D: Glucose metabolism and coronary heart disease in patients with normal glucose tolerance. JAMA291 :1857– 1863,2004
    OpenUrlCrossRefPubMed
  36. Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L, Malmberg K: Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: A prospective study. Lancet359 :2140– 2144,2002
    OpenUrlCrossRefPubMed
  37. Coutinho M, Gerstein HC, Wang Y, Yusuf S: The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care22 :233– 240,1999
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Andany MA, Kasiskie BL: Care of the kidney transplant recipient. Vigilant monitoring creates the best outcome. Postgrad Med112 :93– 108,2002
    OpenUrl
  39. ↵
    Theodoropoulos DS, Shawker TH, Heinrichs C, Gahl WA: Medullary nephrocalcinosis in nephropathic cystinosis. Pediatr Nephrol9 :412– 418,1995
    OpenUrlCrossRefPubMed
  40. ↵
    Jakoby MG 4th, Semenkovich DF: The role of osteoprogenitors in vascular calcification. Curr Opin Nephrol Hypertens9 :11– 15,2000
    OpenUrlCrossRefPubMed
  41. ↵
    Cozzolino M, Dusso AS, Slatopolsky E: Role of calcium-phosphate product and bone-associated proteins on vascular calcification in renal failure. J Am Soc Nephrol12 :2511– 2516,2001
    OpenUrlFREE Full Text
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology
Vol. 1, Issue 3
May 2006
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation
Masako Ueda, Kevin O’Brien, Douglas R. Rosing, Alexander Ling, Robert Kleta, Dorothea McAreavey, Isa Bernardini, William A. Gahl
CJASN May 2006, 1 (3) 555-562; DOI: 10.2215/CJN.01431005

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation
Masako Ueda, Kevin O’Brien, Douglas R. Rosing, Alexander Ling, Robert Kleta, Dorothea McAreavey, Isa Bernardini, William A. Gahl
CJASN May 2006, 1 (3) 555-562; DOI: 10.2215/CJN.01431005
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Proteins in Preservation Fluid as Predictors of Delayed Graft Function in Kidneys from Donors after Circulatory Death
  • Donor-Recipient Weight and Sex Mismatch and the Risk of Graft Loss in Renal Transplantation
  • A Case-Based Analysis of Whether Living Related Donors Listed for Transplant Share ESRD Causes with Their Recipients
Show more Renal Transplantation

Cited By...

  • A Randomized Controlled Crossover Trial with Delayed-Release Cysteamine Bitartrate in Nephropathic Cystinosis: Effectiveness on White Blood Cell Cystine Levels and Comparison of Safety
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2022 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire