Intermediate cystinosis: a case report of 10-year treatment with cysteamine

Abstract

Background

Cystinosis is a lysosomal storage disorder characterized by an autosomal recessive phenotype. Intermediate cystinosis, which progresses slowly and causes renal failure, accounts for approximately 5% of all cystinosis cases. Patients with intermediate cystinosis may not exhibit the typical symptoms of cystinosis, such as Fanconi syndrome and ocular symptoms. Because of its diverse clinical presentation and rarity, intermediate cystinosis can be difficult to diagnose. Additionally, few patients can tolerate cystine-depleting drugs, such as cysteamine, because of their complicated administration schedules and side effects. We report a case of intermediate cystinosis that was treated with cysteamine for 10 years.

Case presentation

Urinary abnormalities were first diagnosed when the patient was 3 years of age during a health examination specifically for 3-year-old children, which is unique to Japan. Cystinosis was diagnosed when the patient was 12 years of age. Cysteamine therapy was initiated and regular cystine concentration measurements were performed. Although proteinuria persisted, the patient’s renal function progressed slowly. Two renal biopsies were performed, and multinucleated podocytes and cystine crystals without focal segmental glomerulosclerosis lesions were observed in the biopsy specimens. The patient’s renal function remained stable.

Conclusions

This case of intermediate cystinosis was treated with cysteamine over the course of 10 years. Intermediate cystinosis requires an appropriate diagnosis and long-term treatment.

Introduction

Cystinosis is a lysosomal storage disorder characterized by an autosomal recessive phenotype that is caused by cystinosin (a lysosomal cystine transporter) dysfunction, which leads to the accumulation of cystine in multiple organs [1]. Cystinosis can be differentiated into nephropathic cystinosis (infantile nephropathic form, Mendelian Inheritance in Man [MIM] #219800), intermediate cystinosis (juvenile nephropathic form, MIM #219900), and non-nephropathic cystinosis (ocular non-nephropathic form, MIM #219750); however, these arbitrary classifications overlap. Patients with nephropathic cystinosis develop end-stage kidney disease (ESKD) by the age of 9 years. Intermediate cystinosis progresses slowly and may lead to ESKD; furthermore, it accounts for approximately 5% of all cystinosis cases [2]. Non-nephropathic cystinosis specifically affects the cornea. Therefore, patients with cystinosis often develop cystine crystals in their eyes that cause light sensitivity (photophobia). The estimated frequency of cystinosis is approximately 1 case out of every 100,000 to 200,000 live births [3]; however, its incidence in East Asia is notably low [4–6]. We performed a survey in Japan and found 17 individuals with cystinosis; of these patients, four had intermediate cystinosis.

Patients with cystinosis often present with Fanconi syndrome and glomerular impairment. Furthermore, renal biopsies of these patients reveal changes in the proximal tubules, multinucleated giant cells, and crystals in interstitial cells and podocytes [7]. Many studies have investigated nephropathic cystinosis; however, reports of intermediate cystinosis are scarce. Patients with intermediate cystinosis may present with proteinuria alone. Additionally, typical corneal findings may be difficult to observe during the early stages of intermediate cystinosis because of the low accumulation of cystine crystals [2, 4]. Consequently, some cases of cystinosis may be overlooked or misdiagnosed [6].

Cystinosis is a rare disease that requires specific treatment. Oral cysteamine treatment depletes lysosomal cystine in all body cells and tissues, improves the prognosis of cystinosis by delaying the progression to ESKD, decreases or delays complications, and improves the life expectancy; however, it does not eliminate cystine crystals from the cornea [8, 9]. Cysteamine bitartrate capsules were approved for use by patients with nephropathic cystinosis in Japan by the Ministry of Health, Labour, and Welfare in 2014. Although oral cysteamine therapy provides significant benefits, such as the delayed need for kidney transplantation and enhanced growth of children, many patients discontinue this treatment because it has an unpleasant smell and taste and can cause nausea, vomiting, and gastrointestinal discomfort [10]. Additionally, the treatment regimen is considered challenging because capsules must be administered every 6 h to prevent a rapid increase in the cystine level [11].

Because an early diagnosis and treatment with cysteamine are required for prolonged renal function and overall survival, the clinical course and characteristics of intermediate cystinosis must be clarified. We report a case of intermediate cystinosis that was treated with cysteamine for 10 years.

Case presentation

A 19-year-old male patient was referred to the Department of Nephrology of our hospital because he was transitioning from pediatric care to adult care. When the patient was 3 years of age, proteinuria and glycosuria were observed during a health examination that is specifically performed in Japan for 3-year-old children. At that time, he initially presented to another hospital, but the causes of proteinuria and glycosuria were unclear. At 12 years of age, he was referred to the initial hospital for further evaluation of an increased beta 2-microglobulin level. Fanconi syndrome and renal dysfunction were diagnosed, and corneal cysteine crystal deposits were suspected. Furthermore, his intracellular white blood cell (WBC) cystine level was increased (6.36 nmol half-cystine/mg protein). Based on these findings, cystinosis was diagnosed [4]. Therefore, cysteamine, which is a cystine-depleting therapy, was initiated. Hypothyroidism developed at 14 years of age, and he was administered levothyroxine. A renal biopsy revealed 63 glomeruli, including four glomeruli with global sclerosis, and multinucleated podocytes (Fig. 1a). Electron microscopy revealed cystine crystals that were observed as clear rectangular spaces (Fig. 1b). A direct sequencing analysis of genomic DNA was performed to detect the CTNS gene and revealed heterozygous single nucleotide substitutions of c.329G > C and c.329 + 2 T > C, which are novel mutations [4].

Fig. 1.

Findings of the first and second renal biopsies. a and b Findings of the first biopsy. c–f Findings of the second biopsy. a Glomeruli with multiple multinucleated podocytes (arrowheads) (hematoxylin and eosin staining). b Cystine crystals are detected as clear rectangular spaces (electron photomicrograph). c A mild increase in the mesangial matrix is observed in some glomeruli (Periodic Acid Schiff reaction). d Many glomeruli exhibit minor glomerular changes (Periodic acid methenamine silver staining). e The glomerulus with multiple multinucleated podocytes (arrowheads) (hematoxylin and eosin staining). f Cystine crystals are detected as clear rectangular spaces (electron photomicrograph)

The patient had no family history of cystinosis. He used cysteamine 2.2 g/day as well as levothyroxine sodium hydrate, potassium citrate, and sodium citrate hydrate. A physical examination revealed a height of 165 cm, weight of 47 kg, and body mass index of 17.3 kg/m². An ophthalmological examination revealed cystine corneal deposits; however, photophobia was not observed. His serum creatinine level was 1.50 mg/dL (estimated glomerular filtration rate, 53.5 mL/min/1.73 m²), and his urinary total protein/creatinine ratio was 0.75 g/gCre. Urinalysis revealed glucosuria with a normal blood glucose level and aminoaciduria (Table 1). His thyroid function remained normal after levothyroxine sodium hydrate administration, and his intracellular WBC cystine level was successfully controlled (0.73 nmol half-cystine/mg protein). Because the patient exhibited good adherence to treatment without gastrointestinal symptoms, cysteamine 2.2 g was considered sufficient for controlling cystine accumulation. Cysteamine eye drops were administered to reduce the density of crystals during follow-up. Although his renal function was stable, proteinuria persisted. Therefore, we decided to re-evaluate the renal status.

Table 1.

Blood and urine findings observed during the initial examination and at the time of the second renal biopsy

Variable	Reference Range	First Visit, This Hospital	Second Biopsy, This Hospital
Blood chemistry
Urea (mg/dL)	8.0–22.0	20.2	20.1
Creatinine (mg/dL)	0.65–1.07	1.50	1.29
eGFR (mL/min/1.73 m2)	60	53.5	61.3
Alb (g/dL)	4.1–5.1	5.0	4.8
Na (mmol/L)	138–145	144	141
K (mmol/L)	3.6–4.8	4.1	4.0
Cl (mmol/L)	101–108	106	107
Ca (mg/dL)	8.8–10.1	9.3	8.8
IP (mg/dL)	2.7–4.6	3.9	2.7
TSH (µU/mL)	0.50–5.00	3.56	3.80
FT3 (pg/mL)	2.30–4.00	3.17	2.63
FT4 (ng/dL)	0.90–1.70	1.64	1.33
Urinalysis
Blood	-	1 +	±
Protein	-	1 +	1 +
Glucose	-	1 +	2 +
Protein/creatinine (g/gCre)	0.00–0.14	0.75	1.00
L-FABP (µg/gCre)	0.0–8.4	132.9	199.4

Conversion factors for units: serum creatinine in mg/dL to µmol/L, × 88.4

Alb albumin, Ca calcium, Cl chloride, eGFR estimated glomerular filtration rate, FT3 free triiodothyronine, FT4 free thyroxine, IP immunoprecipitation, K potassium, L-FABP liver-type fatty acid binding protein, Na sodium, NAG N-acetyl glucosamine, TSH thyroid-stimulating hormone

Two renal biopsies were performed. The first renal biopsy revealed a serum creatinine level of 1.29 mg/dL and urinary total protein/creatinine ratio of 1.0 g/gCre. Light microscopy revealed 35 glomeruli; of these, two exhibited global sclerosis. A mild increase in the mesangial matrix was observed in some glomeruli, but many exhibited minor glomerular changes (Fig. 1c, d). Furthermore, the glomeruli did not exhibit focal segmental glomerulosclerosis (FSGS). The second renal biopsy also showed multinucleated podocytes in some glomeruli (Fig. 1e). Interstitial fibrosis affected approximately 10% of the cortical area. Immunofluorescence revealed nonspecific partial deposition of IgM and C3 on the capillary wall. Electron microscopy detected only one cystine crystal as a clear rectangular space (Fig. 1f). The patient continued to undergo outpatient examinations at our department after the second renal biopsy and exhibited controlled cystine concentrations. Although proteinuria persisted, his renal function remained stable for 5 years and new complications were not observed (Fig. 2a, b).

Fig. 2.

Changes in creatinine and proteinuria over time. a Symptom onset and treatment began at age 3 years. Cystinosis was diagnosed at age 12 years. Treatment was initiated at age 12 years and continued for 10 years. b The graph shows the course of the disease from the time of diagnosis to age 22 years. Although proteinuria persisted, the estimated glomerular filtration rate (eGFR) slowly declined

Discussion and conclusions

Compared with that of nephropathic cystinosis, the clinical presentation of intermediate cystinosis varies; therefore, its diagnosis is often difficult. Although intermediate cystinosis slowly progresses and results in the gradual onset of renal disease, some patients may experience ESKD because their diagnosis is delayed or they cannot tolerate cysteamine. Furthermore, cysteamine may not prolong the life expectancy of some patients.

Our patient was diagnosed with cystinosis based on the presence of Fanconi syndrome, proteinuria, and corneal cystine deposition [4]. The patient was treated with cysteamine for 10 years, and two renal biopsies, which revealed the characteristic findings of cystinosis, were performed. Successful long-term treatment of this case was attributable to the specific health examination performed in Japan for 3-year-old children, which contributed to the early diagnosis of intermediate cystinosis, the use of cysteamine for 10 years and follow-up evaluations, and pathological re-evaluation of renal lesions during cysteamine treatment. This is the first case report of intermediate cystinosis observed in a patient in Japan. These findings are clinically useful to the successful diagnosis and treatment of intermediate cystinosis.

Intermediate cystinosis is associated with diverse clinical presentations and can occur at various ages. A previous study of 14 patients (from nine families) with intermediate cystinosis [2] reported that the age of onset ranged from 4 to 30 years, and that the age at the time of diagnosis ranged from 6 to 50 years. For three of these patients, the interval between disease onset and diagnosis was more than 10 years. Some patients experienced symptoms similar to those of nephropathic cystinosis, such as ocular lesions, Fanconi syndrome, and rickets; however, some patients experienced asymptomatic proteinuria alone. A family history could be an important clue to the diagnosis; however, some patients do not have a family history of cystinosis.

Our patient did not exhibit growth restriction; however, proteinuria and glycosuria were detected during the health examination for 3-year-old children. Although cystinosis was not diagnosed at that time, it was suspected as the cause of Fanconi syndrome when the patient was 12 years of age. The corneal findings revealed by the ophthalmological examination were crucial to the diagnosis. Because the patient did not report photophobia, his clinical presentation was unremarkable before the urinalysis was performed. In Japan, specific health examinations are performed in schools and for 3-year-olds. These examinations allow additional opportunities to identify rare diseases, such as intermediate cystinosis, that are difficult to diagnose.

Currently, the only treatment for cystinosis is oral administration of cysteamine [2]. Early and continuous treatment with cysteamine, particularly for renal-type cystinosis, can delay end-stage renal failure and the onset of complications and prolong the life expectancy [8, 9, 12]. Early initiation of cysteamine treatment not only improves the quality of life and renal outcomes but also offers substantial economic health benefits by delaying the need for dialysis. A previous study reported that the cysteamine dosage is related to the mean leukocyte cystine level, but not to the age at the time of renal failure [13]. However, it is difficult to adequately administer cysteamine because of its distinctive odor that is similar to sulfur and adverse gastrointestinal symptoms [10]. Additionally, cysteamine should be continued not only during childhood but also during adolescence and adulthood; however, poor treatment adherence during the transition period from childhood to adulthood is a major challenge. Although nephropathic cystinosis develops during childhood, intermediate cystinosis may occur during adulthood; therefore, the transition from pediatric care to adult care is important for pediatric cases [14].

The cystine assay plays a crucial role in the diagnosis and therapeutic monitoring of cystinosis. The detection of an increased cystine level in WBCs is considered the primary indicator of cystinosis; additionally, the cystine level in WBCs is used to assess the effectiveness of cystine-depleting therapy. We believe that discussing the results of adherence to treatment with patients can help them maintain a sense of self-efficacy. Fortunately, our patient continued treatment without any major side effects.

To the best of our knowledge, there have been few documented cases of intermediate cystinosis that were evaluated using renal biopsy [2, 6, 15, 16]. Furthermore, renal biopsies are rarely performed during cysteamine treatment. Servais et al. reported a case for which a second biopsy was conducted before cysteamine administration [2]. Our case is both unique and valuable because renal biopsy was conducted at the time of diagnosis and during a subsequent evaluation after nearly 10 years of treatment. Renal biopsies of patients with cystinosis may reveal FSGS and chronic tubular lesions; however, these findings are nonspecific. Cystinosis may be misdiagnosed as idiopathic FSGS, other tubular diseases, or as an unknown cause [6]. Cystine crystals can be observed only with alcohol fixation; however, crystals are not observed in some cases [2]. Multinucleated podocytes are a distinctive finding that may indicate cystinosis; however, they have been observed with other glomerular diseases, such as minimal change disease, IgA glomerulonephritis, lupus nephritis, and diabetic nephropathy [6, 17, 18]. Multinucleated podocytes result from nuclear division without cytokinesis. Normal podocytes are highly differentiated and postmitotic. Podocyte injury typically results in foot process effacement, detachment from the glomerular basement membrane (GBM), and podocyte death [19]. Injured or stressed podocytes may re-enter the cell cycle from the G0 phase to the M phase [18, 20]. Because podocytes cannot undergo cytokinesis or complete cell division, the formation of multinucleated podocytes occurs. However, they are unstable and may detach from the GBM [19]. Podocyte detachment and denudation of GBM may cause FSGS lesions [21]. A previous study reported that the urine of patients with cystinosis comprises more podocytes than the urine of healthy controls [22]. Podocyte detachment may be related to foot process effacement and proteinuria [23]. Patients with heavy proteinuria may exhibit FSGS, which implies cystinosis [21].

The first renal biopsy revealed multinucleated podocytes and cystine crystals, which are findings compatible with cystinosis. Although the patient’s renal function slowly progressed, proteinuria was sustained at approximately 1 g/gCre. The second biopsy was performed after 9 years of treatment, and multinucleated podocytes were observed. However, some global sclerosis and interstitial fibrosis without FSGS lesions were observed. Fewer podocytes with three or more nuclei were observed during the second biopsy (0.18 per glomerular cross-section vs. 0.27 per glomerular cross-section observed during the first biopsy). These findings reflect the clinical course.

The relationships between multinucleated podocytes, glomerular lesion progression, and the effects of cysteamine require further research. However, our case illustrated that early diagnosis and long-term treatment of intermediate cystinosis are important to a good renal prognosis.

Abbreviations

FSGS

Focal segmental glomerulosclerosis

MIM

Mendelian Inheritance in Man

ESKD

End-stage kidney disease

WBC

White blood cell

GBM

Glomerular basement membrane

Authors’ contributions

MK and DK designed and performed the study and drafted the manuscript. YY, KS, TH, YS, and TO managed the patient during hospitalization. SH, MO, NU performed histological analysis. The final manuscript was read and approved by all authors.

Funding

This study was supported by grants from the Japan Society for the Promotion of Science (grant number 23K07687) and the National Center for Global Health and Medicine (22A1006, 24A1012). The funders played no role in the study design, data collection and analysis, interpretation, writing of the manuscript, or decision to publish.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) of the National Center for Global Health and Medicine on 3/8/2019 (IRB approval number: NCGM-G-001847-04). This study was conducted in accordance with the principles of the Declaration of Helsinki and the CARE guidelines.

Consent for publication

Written informed consent was obtained from the patient for the publication of de-identified data and histopathological images.

Competing interests

The authors declare no competing interests.