Updated: Aug 28, 2022
Sai Santhoshini Achi, MD MBA (@SaiAchi1)
Figures by Sophia L Ambruso, DO (@Sophia_kidney)
Cystinosis, first described in 1903, is a rare autosomal recessive disorder characterized by the intracellular accumulation of cystine in tissues and organs. It affects about 1 in 100,000-200,000 people in the general population,occurs in all ethnic groups, and affects males and females equally. Cystinosis accounts for about 5% of renal failure in children and is the commonest cause of renal Fanconi syndrome in children.
Cystinosis is caused by mutations in the CTNS gene which codes for the protein, cystinosin, – a hydrogen ion-driven transporter that removes cystine from lysosomes. Although cystinosis is associated with numerous mutations, the most common is a 57,257-bp deletion which is found in 50% of patients from a northern European descent. These mutations cause a defect in cystinosin, leading to a cystine accumulation and subsequent crystallization that occurs during protein degradation transport. (1)
In normal physiology, the lysosomes are membrane bound compartments which break down nutrients such as fats, carbohydrates, and proteins. After the breakdown process, some enzymes metabolize these nutrients whereby other enzymes transport products like cystine from the lysosomes throughout the body. It is when this transporter is deficient that cystinosis occurs and leads to a buildup of cystine in the lysosomes.
Figure 1. Pathophysiology of cystinosis
Cystinosis can be characterized into three subcategories:
(i) Infantile Nephropathic Cystinosis
(ii) Intermediate Cystinosis
(iii) Non-Nephropathic Cystinosis
Infantile nephropathic cystinosis (also called nephropathic cystinosis) is the most severe form and typically presents by 6 months of age with Fanconi syndrome, nausea and vomiting, failure to thrive, feeding difficulties, electrolyte disorders, and vitamin D resistant rickets.
Renal involvement is predominantly Fanconi’s, which results in downstream complications, if untreated, like the development of polyuria and dehydration, renal tubular acidosis (RTA) (from bicarbonate loss) and impaired bone development (from phosphate loss) manifesting as Rickets disease and osteomalacia. Patients subsequently display decreased growth velocity and chronic kidney disease (CKD). End stage kidney disease (ESKD) can develop by the first decade of life.
Extra renal involvement may include the eyes, liver, spleen, and muscle. Myopathies may also result due to accumulation of cystine in muscles as well. The figure below illustrates the systemic effects of nephrogenic cystinosis.
Figure 2. Clinical Presentation of Nephropathic Cystinosis
Intermediate Cystinosis presents in late childhood or adolescence with variable features like mild Fanconi syndrome, proteinuria, and a slower rate of CKD progression. They typically display no growth restriction.
The non-nephropathic cystinosis is a form of cystinosis that affects adults during middle age and affects only the eyes and untreated patients may develop corneal cystine accumulation.
Diagnosis of cystinosis:
Early diagnosis of cystinosis is important as it shapes the clinical outcomes of patients. Three main modalities of diagnosis include:
(i) elevated cystine levels in leukocytes (WBCs) (gold standard)
(ii) molecular testing of CTNS genes
(iii) detection of corneal cystine crystals by way of slit lamp exam
The measurement of cystine levels in WBCs to diagnose cystinosis was described in 1974; the current methodology involves use of liquid chromatography mass spectrometry or liquid chromatography and the use of assays that bind cystine in the WBCs to cystine binding proteins. In patients with newly diagnosed cystinosis, WBC cystine levels are around 20 nmol half-cystine/mg protein whereas control levels are usually <1 nmol half-cystine/mg protein.
Genetic testing for CTNS variants is the confirmatory testing by which cystinosis may be diagnosed.
Amniotic fluid and chorionic villus sampling can facilitate prenatal diagnosis of cystinosis in infants identified to be at risk as well.
Detection of corneal cystine crystals is another method to diagnose cystinosis. It is used in developing countries, is relatively reliable and is cost effective in detection of corneal cystine crystals. However, one pitfall of this method is that cystine crystals typically appear in the second year of life, whereby relying on this method of detection may delay diagnosis and therapy.
Figure 3. Typical structures of the cystine stones are hexagonal shaped and with linear margins. https://www.renalfellow.org/2020/03/28/urine-sediment-of-the-month-cystine-crystals/
Cysteamine bitartrate was FDA approved for treatment of cystinosis in 1994. In 2013, procysbi, an extended form of cysteamine, became available. Cysteamine depletes cystine, lowering cellular levels, thereby slowing the progression of disease, which is highlighted by the figure below. Cysteamine is administered orally and required lifelong. The oral formulation does not address corneal cystinosis, which must be treated by Cystaran, an ophthalmic solution that targets crystal accumulation in cornea.
Figure 4. Cysteamine mechanism of action
Side effects of cysteamine
Notable side effects can include: leukopenia, ulcers, severe skin rashes, idiopathic intracranial hypertension and patients complain of halitosis, abdominal discomfort, nausea, vomiting, poor appetite. In pregnancy, accumulation of cystinosis can affect the uteroplacental function.
Teratogenicity of cysteamine
Cysteamine has been seen to have potential teratogenicity in animals but the extent to which that translates to humans is unknown due to lack of adequate studies in pregnant women. Reported findings include cleft palate, kyphosis, heart ventricular septal defects, microcephalic and exencephaly.
Symptomatic management is key in treating cystinosis and an interdisciplinary approach with a specialist team including: pediatricians, nephrologists, ophthalmologists, etc.
Of note, patients receiving a kidney transplant do remarkably well with the curation of Fanconi syndrome respond very well and have had their renal Fanconi syndrome be cured due to lack of cysteine accumulation in the transplanted kidney; there have been some cases which show that there may be benefit in continuing the cysteamine even post renal transplant.
Cystinosis in pregnancy:
The option of cystine-depleting therapy (cysteamine) and kidney transplant have contributed to improved life expectancy, restored fertility and increased pregnancy considerations among those with cystinosis. However, teratogenic effects of cysteamine in humans is not known (but well-documented in animal studies) necessitating discontinuation during pregnancy, thereby presenting surveillance and management challenges throughout the course of pregnancy and during the breastfeeding period. We present to you two cases published in KI Reports on pregnancy and breast feeding in mothers diagnosed with cystinosis.
This brings us to a case of chronic kidney disease published in KI Reports, cystinosis and late adolescent pregnancy resulting in the delivery of a healthy baby from a non-dialysis dependent mother. Due to its teratogenicity, cysteamine was discontinued. Throughout the duration of pregnancy, the mother was closely monitored and managed by a multidisciplinary kidney and obstetrical team co-managed and optimized her electrolytes with close monitoring of blood pressure, kidney function, electrolytes, and urine protein. replacement including oral phosphate, potassium chloride, calcium carbonate and sodium bicarbonate. During the mid-pregnancy fetal growth spurt and peridelivery, more pronounced electrolyte derangements were observed, specifically hypokalemia and hypophosphatemia, and associated supplementation required, with intravenous electrolyte requirements in the peridelivery period. The mother delivered a healthy male infant without evidence of cystinosis or features of renal Fanconi syndrome. After much discussion and deliberation, the patient was advised for breastfeeding as the benefits outweighed the risks in an environment with low resources.
The figure below highlights the dosing of her electrolytes throughout the course of pregnancy.
Figure 5. Supplemental electrolyte doses throughout pregnancy
Breastfeeding and Cystinosis
There is a paucity of data surrounding the safety of cysteamine while breastfeeding, therefore, few recommendations exist to guide practitioners and mothers. We present another case published in KI Reports of a 24-year old patient with a history of infantile nephropathic cystinosis and CKD stage G2A3 with a successful pregnancy and breastfeed experience. The patient presented at 18 weeks gestation with a creatinine level of 76 µmol/L (0.86 mg/dL). Cysteamine was discontinued due to its teratogenic effects. During her pregnancy, her leukocyte cystine level rose from 1.22 to 3.27 nmol cystine per mg protein. Proteinuria and eGFR increased during pregnancy. Patient suffered electrolyte abnormalities related to Fanconi and prepregnancy electrolyte supplementation included potassium, phosphate and sodium bicarbonate. During pregnancy, potassium and phosphate supplementation increased (no changes to bicarbonate were required). The patient successfully delivered at 33 weeks via spontaneous vagin
al delivery and admitted to NICU. Two months after delivery, serum creatinine was 95 µmol/L (1.1 mg/dL) . Cysteamine was initiated immediately postpartum. During breastfeeding, cysteamine was dosed at a delayed release dose of 675 mg twice daily compared to 825 mg twice daily pre-pregnancy. The breastmilk data was collected and showcased in the figure below, demonstrating relatively low cysteamine levels.
The table below tracks the patient’s breastmilk cysteamine levels.
The case brings to attention the importance of counseling and shared decision making and that breast milk contains low amounts of cysteamine and likely are not clinically significant which could be a potential reassurance for patients with cystinosis who would like to breastfeed. It is one of the few case reports that depicts a successful pregnancy in patients with cystinosis as other case reports had noted significant complications. The table below highlights some case series and their cystinosis related maternal and fetal outcomes. Cysteamine treatment and its excretion in the breast milk is not fully known; some guidelines show that breastfeeding is not recommended whereas other studies show that toxicity is not likely given the amount of the cysteamine in the breast milk is not substantial. Further studies are necessary to understand the safety of cysteamine and breastfeeding.
Table 2. Summarized case series of maternal and fetal outcomes in cystinosis-related pregnancies.
Figure 6. Cysteamine in pregnancy and breastfeeding
Take Home Message
1. Cysteamine should not be prescribed during pregnancy
2. A multidisciplinary approach is important in pregnant patients with cystinosis with close monitoring of kidney function, electrolytes
3. Cysteamine at reduced doses may be safe during breastfeeding where only low levels are detected in breastmilk
4. There is much to be studied in terms of cystinosis and pregnancy and breastfeeding