Cystinosis Treatment & Management

In the past, the treatment of cystinosis was limited to treating metabolic acidosis and, often, replacing electrolytes lost in the urine; later during the course of the disease, chronic kidney disease (CKD) was treated. ^[4] Today, the wide availability of an effective drug, phosphocysteamine, and kidney replacement therapy with transplantation has dramatically improved the outlook for patients and altered management strategies.

• Replacement of urinary losses: The child must be well-hydrated and administered supplements of potassium and bicarbonate, as needed. Rickets should be treated with vitamin D and phosphate supplementation. Carnitine may also be needed because its excretion is particularly elevated in the urine, and muscle levels have been documented to be reduced. Particular care should be given to fluid and electrolyte therapy during intercurrent episodes of fever, vomiting, or diarrhea.

• Management of volume depletion/dehydration states

  • Initial management of volume depletion in a child with cystinosis requires administration of large amounts of fluids and electrolytes, often exceeding conventionally defined limits. Fluid requirements may be more than twice that expected for the patient's size.

  • Urinary losses must be carefully monitored and replaced during hospitalization.

  • The rehydration fluid should contain glucose, sodium, potassium, and bicarbonate (in amounts generously exceeding the standard intravenous fluid composition). The concentration of these substances should be adjusted on the basis of frequently measured serum laboratory values.

  • After rehydration is accomplished, maintaining free access to water or other fluids is important because patients with cystinosis easily become dehydrated. For example, place a water container at the bedside during the night.

  • When the patient becomes free of acute GI symptoms (ie, no longer having frequent episodes of vomiting, gagging, abdominal pain, or diarrhea) and is able to eat well, restart the patient on a regular diet, supplementing individually determined amounts of sodium, potassium, bicarbonate, and phosphate to achieve reference range serum levels.

• Cysteamine therapy

  • Delayed-release cysteamine bitartrate (Procysbi) is available for the management of nephropathic cystinosis, the most severe form of the rare genetic disorder cystinosis, in patients aged 2 years and older. Its approval was based on a study that showed the delayed-release formulation (q12h) was as effective as the immediate-release formulation (Cystagon) (q6h) in controlling cystine levels in 43 children aged 6 years or older and adults with nephropathic cystinosis. An extension of this trial enrolled 13 children aged 2-6 years who converted from immediate-release cysteamine to delayed-release. Mean WBC cystine decreased from 1.4 nmol to 1.13 nmol. Seven of the 13 patients achieved < 1 nmol. ^[5]

• Indomethacin therapy

  • Indomethacin may limit water losses in patients with nephropathic cystinosis by both reducing the glomerular filtration rate (GFR) and by sensitizing the collecting duct to the effects of antidiuretic hormone. It has been used to treat patients with cystinosis more commonly in Europe than in the United States. In uncontrolled clinical reports, indomethacin has been shown to relieve polyuria and polydipsia and to improve appetite, energy, and general well-being by reducing urinary losses of water and other various substances.

  • Indomethacin therapy requires careful monitoring of kidney function because the GFR may be worsened by the administration of this drug.

  • The ulcerogenic potential of indomethacin is its major drawback for treating cystinosis.

• Growth hormone therapy

  • Treatment with recombinant human growth hormone improves growth velocity. Long-term recombinant human growth hormone treatment in young children with nephropathic cystinosis prior to renal replacement therapy is safe and efficient.

  • Growth hormone treatment is less effective for peripubertal or adolescent patients on renal replacement therapy.

  • Treatment with recombinant human growth hormone does not accelerate a decline in kidney function in children with chronic kidney disease.

• Thyroid replacement: This is indicated in patients diagnosed with hypothyroidism.

• Kidney transplantation: Kidney transplantation in patients with infantile cystinosis corrects kidney failure and prolongs survival (the donor parenchymal cells are not homozygous for the genetic defect and are therefore able to transport cystine from the lysosomes). However, transplantation does not prevent progression of the disease in other nonrenal organs, and therapy with oral cysteamine is indicated in patients after kidney transplantation. Management of cystinosis with oral Cystagon must be initiated as soon as diagnosis of cystinosis is made.

• Management of corneal cystine crystals

  • Ocular complications associated with deposition of corneal cystine crystals include photophobia, eye pain, squinting, corneal haziness and foreign body sensations. Severe cystine crystal accumulation can damage the cornea, resulting in serious vision difficulties. Oral cysteamine is not distributed into the eye and thus has no impact on corneal crystal accumulation.

  • Cysteamine ophthalmic solution 0.44% (Cystaran) was approved by the US Food and Drug Administration (FDA) in October 2012 for corneal cystine crystal accumulation in patients with cystinosis. ^[6] Corneal crystals reaccumulate if cysteamine ophthalmic solution is discontinued.

Images demonstrating the course of cystinosis are shown below.

Nephrologists usually diagnose cystinosis as the cause of Fanconi syndrome.

The patient must be referred to an ophthalmologist upon initial evaluation and at subsequent regular intervals.

Regular follow-up by pediatric nutritionist is recommended in patients with poor growth.

A pediatric endocrinologist may provide follow-up care for the patient related to growth hormone therapy, thyroid insufficiency, or diabetes mellitus.

Patients with recurrent abdominal pain, poor feeding, or vomiting and/or diarrhea should be evaluated by a gastroenterologist to diagnose the nature of GI abnormalities (eg, swallowing dysfunction, gastroesophageal reflux, delayed gastric emptying, gastric/duodenal ulcer, pseudo-obstruction).

Some children may require follow-up care by a behavioral therapist or a dietitian, depending on the child's needs.

Because of various neuromuscular problems, patients in late adolescence require follow-up by a neurologist.

Patients should be referred to an early intervention program to evaluate and treat common fine-motor movement and coordination delays.

Some patients with severe gastroesophageal reflux may require gastric/jejunal tube placement or Nissen fundoplication to achieve optimal nutrition.

Diet

Dietary recommendations should follow daily Dietary Reference Intake (DRI) requirements (ie, 60% carbohydrate, 10% protein, 30% lipids), and caloric intake should aim to achieve weight gain. If the patient is a poor eater and oral feeding is unsuccessful, high-calorie oral supplements should be administered. If the patient does not take supplements or has an inappropriately low intake because of poor appetite or vomiting, gastric tube placement can help.

Total parenteral nutrition is indicated if a cystinotic patient cannot tolerate any form of enteral feeding. Some patients may need additional therapy with agents improving GI kinetics or antagonists of acid production.

Activity

Because of the chronic nature of the disorder, parents should try to accommodate the child's medical needs, while allowing the child to grow and develop similar to healthy children. Parents should encourage play and group participation.