The first case of nephropathic cystinosis was reported in the literature in 1903. Since then, researchers have discovered much about the disease, yet it remains incurable and continues to greatly shorten the life expectancy of affected individuals. Nephropathic cystinosis is a rare autosomal recessive lysosomal disorder caused by any of a hundred or more inherited mutations in the CTNS
gene. The CTNS
gene encodes the transporter protein cystinosin, which is responsible for transporting the amino acid cystine out of the lysosome. Some mutations, such as the 57-kb deletion, result in complete loss of cystinosin, whereas other mutations are associated with production of an insufficient amount or a less functional form of the protein.
Cystine accumulates and crystalizes in the lysosome of every cell, causing progressive damage to multiple organs, especially the kidney. Although the pathophysiology of cystinosis is not fully understood, the deficiency in cystinosin has other systemic effects. Cystine accumulation begins in utero, and 50 years ago, a child born with nephropathic cystinosis typically experienced fatal end-stage renal disease (ESRD) before 10 years of age. Today, advances in medical treatment have allowed some patients to survive into their 50s.
Experts in nephropathic cystinosis agree that prolonged survival depends on early diagnosis and treatment. In an interview with Rare Disease Report, Craig B. Langman, MD, Division of Kidney Disease, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, explained that there are 3 clinical forms of cystinosis, defined by age of onset: infantile, juvenile or late onset, and adult onset. Infantile cystinosis accounts for more than 90% of cases and is the most common cause of Fanconi syndrome, which is typically observed when the child is between 3 and 6 months old.
"The infant form of cystinosis is not always recognized promptly, and some children die of recurrent dehydration," Langman said. "The late-onset or adolescent form of cystinosis accounts for about 5% of cases and is very under-recognized," he said. This form typically presents between 10 to 12 years of age but may occur in late adolescence or early adulthood. Although Fanconi tubulopathy is milder with late-onset disease, proteinuria is more pronounced. "Importantly, many patients present with focal segmental glomerulosclerosis (FSGS), and cystinosis should be included in the differential diagnosis for juveniles with FSGS," Langman advised. Unlike infantile cystinosis, which progresses to ESRD within 10 years, patients with adolescent-onset cystinosis typically do not experience ESRD until their late 20s.
Langman expressed concern that most nephrologists who treat adults do not recognize late-onset cystinosis and described some of the non-renal manifestations. "Cystinosis is systemic, and patients with late-onset disease will often have other more subtle signs and symptoms, such as hypothyroidism, photophobia, muscle dysfunction, and myopathy." The third form of cystinosis is an ocular subtype caused by crystallized cystine deposits in the cornea and conjunctiva and presents in adulthood but without the usual kidney impairment. Ocular involvement is evident in all patients with cystinosis, and a slit lamp examination after age 1 will usually reveal corneal crystals. Ocular cystinosis does not respond to the systemic therapies prescribed for nephropathic cystinosis and is instead treated with prescribed drops. Photophobia may occur with increased ocular involvement.
In the 1960s, children with cystinosis began to receive kidney transplants for renal failure. Kidney transplants extend life but are not curative; the transplanted organ is subjected to the same destructive process as the kidney it replaced. Researchers began experimenting with oral cysteamine bitartrate in the 1970s, which was approved in the 1990s as Cystagon in Europe and the United States. Cysteamine reacts with cystine in the lysosome to form a complex the body can clear from the cells.
Langman said no one has conducted a prospective controlled trial to evaluate how cysteamine affects survival. However, since the drug was introduced, a number of patients who started on it as young children are now adults. "We believe more than half the patients living with cystinosis today are adults. With good care, we believe we can help people survive into their late 30s and early 40s and possibly longer if treatment is started earlier," said Langman. "My oldest patient is in her 50s." Retrospective studies show patients who start cysteamine early and are highly adherent may delay ESRD and the need for transplant. He noted, however, that although cysteamine successfully depletes cystine, most patients still require a kidney transplant at some point, which suggesting that scientists do not fully understand the mechanism of the disease.
Immediate-release cysteamine is an effective treatment for slowing some of the consequences of cystinosis, but Langman said many factors make it hard for patients to stick with their treatment. "The immediate-release version must be taken every 6 hours or organ damage starts to occur...patients have to interrupt their sleep every night to take this drug." Parents are diligent about administering it to their babies, but it becomes increasingly difficult as the children age. "Gastrointestinal upset is another problem with Cystagon. At peak exposure, stomach acid secretions increase," he explained. Patients also have increases in brain-mediated gastric secretions and the upsetting cystine deposits in the stomach. "Most patients on Cystagon take some form of acid-reducing therapy, such as a proton pump inhibitor," Langman said. Another undesirable consequence of cysteamine use is a sulfurous "rotten egg" smell patients emit as the drug is metabolized.
Langman and colleagues began researching a delayed-release version of cysteamine that they believe may improve adherence and quality of life. "The initial study was a randomized, crossover, nonblinded trial that compared delayed-release cysteamine (DR-CYS) with immediate-release cysteamine for noninferiority," Langman said. (Langman CB, et al. Clin J Am Soc Nephrol
; 2012;7:1112-1120) An obvious benefit of DR-CYS for patients is that it only has to be taken every 12 hours.
The trial, which enrolled 41 patients aged 6 to 21 years, proved DR-CYS was just as effective as immediate-release cysteamine and the manufacturer, Raptor Pharmaceuticals, decided to seek approval. In 2013, the US Food and Drug Administration and the European Medicines Agency approved DR-CYS—marketed as Procysbi—to treat nephropathic cystinosis in individuals 6 years and older. Forty patients (mean age, ~12 years) who completed the short-term efficacy study enrolled in a prospective 2-year, open-label, phase 3, maintenance trial of DR-CYS. Outcomes included preservation of kidney function, growth stability, and quality of life (QOL). Adverse effects were also evaluated. Results were recently published in the Journal of Pediatrics
. (Langman CB, et al. J Pediatr
Langman said the trial showed improvement in 3 of 5 function scores on the Pediatric Quality of Life Inventory and no deterioration in the other 2 QOL measures. Patients who crossed over from immediate-release cysteamine to DR-CYS had significant improvement in social function (P
=.049), school function (P
=.004), and total function (P
=.048). Emotional and physical function remained unchanged. Langman said most patients did not have any sulfur odor while taking DR-CYS, which may have contributed to some of the QOL improvements, along with the fact that they only had to take the drug every 12 hours.
Cystine levels in patients with cystinosis are measured in the white blood cells (WBCs). Langman said the target of treatment is to get the WBC cystine level to <1 nmol half-cystine/mg of protein, which is the level observed in individuals with 1 mutation and no clinical manifestations. Without treatment, patients with cystinosis have WBC cystine levels >2 nmol half-cystine/mg of protein. Throughout the trial, the mean WBC cystine level was consistently maintained <1 nmol half-cystine/mg of protein. Levels remained stable despite a significant reduction in the mean dose of DR-CYS from 43.5 mg/kg/d at study entry to 40.1 mg/kg/d at the end of the study. Investigators observed no significant changes in the estimated glomerular filtration rate, supporting the earlier findings of noninferiority with DR-CYS. "Over time, we were able to keep WBC cystine levels lower using less cysteamine. The amount of drug taken over 24 hours is a lot less with DR-CYS," Langman said.
Cystine deposits crystals in the bone, and children with cystinosis often have impaired growth and rickets, especially if they did not start treatment promptly. Children in the study who were not taking growth hormone experienced stable growth (height and weight) with DR-CYS. No serious or unexpected treatment-related adverse events were observed and patients the monthly rate of adverse events declined from 0.30 per individual per month in the trial that included an immediate-release cysteamine arm to 0.06 per individual per month at 24 months in the single-arm study. All the patients, however, had at least 1 adverse event, and 87.5% reported a gastrointestinal disorder. Most developed emesis (70%); other common adverse events were headache (35%), upper respiratory tract symptoms (23%), and diarrhea (20%). Langman said "Only 1 of 30 patients was unable to stop taking a PPI."
Most of Langman's US patients participated in the trial. "None of the patients have said they want to go back on Cystagon, and they all seem happy with having a 12-hour drug." A trial in non-US patients is ongoing, and the investigators have started 2 additional trials. One is evaluating a dose of DR-CYR sprinkled on applesauce for patients younger than 6 years old. The other is a 1-year trial of DR-CYS in treatment-naive patients, most of whom are infants.
Langman said one of his concerns is that as cysteamine has transformed the natural history of cystinosis from a deadly childhood disease to one where children survive well into adulthood, the negative effects of cystinosin deficiency on other organs and tissues is becoming more apparent. Adults with cystinosis develop pulmonary dysfunction, diabetes, muscle weakness, myopathy, and vascular calcification, although good adherence to treatment lessens the likelihood of some extra-renal complications. "Physicians do not know as much about how this disease affects adults. As children with cystinosis age, who will take care of them?"
Langman recently co-chaired the first rare kidney disease conference held by KDIGO (Kidney Disease Improving Global Outcomes), which was on nephropathic cystinosis. He believes the involvement of KDIGO (www.kdigo.org) will help educate adult practitioners on the disease, for which no official treatment guidelines yet exist.
Rare Diseaes Quick Facts: Nephropathic Cystinosis
An estimated 5600 people in the United States and 20,000 people worldwide have nephropathic cystinosis
The prevalence of nephropathic cystinosis is 1:100,000 to 1:200,000
The kidneys of people with nephropathic cystinosis have 200 to 400 times the normal amount of cystine
Cystinosis is more common in people of Western European descent (especially blond, blue-eyed individuals)