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

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.

Hematological Manifestations of Nephropathic Cystinosis

“…In contrast, oral cysteamine therapy represents an attractive targeted therapeutic modality. Long-term oral cysteamine administration in patients with cystinosis [4] has been shown effective in decelerating glomerular deterioration [16, 17], eliminating signs and symptoms of encephalopathy and the gross abnormalities on MRI [18], depleting cystine in parenchymal organs (liver and muscle) [19], and lowering the frequency of hypothyroidism [20], swallowing abnormalities [21], coronary artery and other vascular calcifications [22], and posterior eye segment defects [23]. As we view cystine accumulation in the bone marrow a likely contributor to this patient’s pancytopenia, oral cysteamine administration represents the promising available therapy.…”

Nephropathic cystinosis: late complications of a multisystemic disease

“…Blood pressure usually returns to normal after removal of the native kidney. Calcification of various vessels, primarily the coronary arteries, is one of the late complications of cystinosis in patients with transplants [106]. High-resolution CT scans have revealed calcifications in the internal carotid arteries, coronary arteries, aortic arch and abdominal aorta.…”

“…Most patients with vascular calcifications had not received significant cysteamine therapy, which is consistent with the conclusion that cystinosis itself, and not drug exposure, is a risk factor for this complication. Adult patients should be carefully monitored for myocardial ischemia; some may require stenting or bypass surgery [106]. The hypercholesterolemia of cystinosis [107] also puts patients at increased risk of developing cardiovascular complications.…”

“…5) and feeding difficulties [14]. The vascular calcifications associated with cystinosis occurred far more often in patients who did not receive cysteamine therapy than in those who did [106]. Finally, normal adult height can be achieved by cystinotic patients who receive oral cysteamine therapy from early childhood; we know of several well-treated young adults with heights between 168 cm and 188 cm.…”

Non‐invasive measurements of atherosclerosis in adult cystinosis patients

“…Ueda et al found increased coronary and vascular calcifications in cystinosis patients and hypothesized that the accumulation of intracellular cystine itself may be a risk factor for vascular calcifications. They advised to screen older patients with cystinosis for this complication (Ueda et al 2006). We hypothesize that cystine accumulation in blood vessels might increase atheroma formation or arterial stiffness and therefore increase the risk for cardiovascular disease CVD.…”