Objectives: Cystinosis is a rare autosomal recessive lysosomal storage disorder causing progressive chronic kidney disease. Limited data exist on renal transplant outcomes in transplant recipients with cystinosis. In this study, we compared clinical outcomes of pediatric renal transplant recipients with cystinosis versus those without cystinosis.
Materials and Methods: We conducted a retrospective comparative analysis of 143 pediatric renal transplant recipients (23 with cystinosis, 120 without cystinosis [control group]) followed at a Kuwait kidney transplant center. Primary outcomes included graft function, patient survival, and posttransplant complications. Secondary outcomes assessed anthropometric parameters and serum creatinine trajectories.
Results: Transplant recipients with cystinosis versus without cystinosis had significantly lower height at last follow-up (1.34 ± 0.18 vs 1.52 ± 0.15 cm; P = .⁰⁰¹) and better baseline renal function (creatinine level of 84.5 ± 36.4 vs 105.0 ± 89.0 μmol/L; P = .⁰⁴). Graft survival at final follow-up was comparable between groups (78.3% in cystinosis group vs 69.2% in control group; P = .³⁹). New-onset diabetes after transplant was not observed in the cystinosis group versus shown in 9.2% of patients in the control group (P = .¹⁷). Viral complications, including BK viremia, BK nephropathy, and cytomegalovirus viremia, showed no significant difference between groups. Patient survival was excellent in both groups (100% vs 98.3% in the cystinosis vs control group; P = .⁵⁵).
Conclusions: Pediatric renal transplant recipients with cystinosis demonstrated comparable graft survival and favorable posttransplant outcomes versus recipients without cystinosis, with potential advantages, including lower incidence of new-onset diabetes after transplant and better early renal function. These findings support renal transplant as a viable treatment option for pediatric patients with cystinosis and end-stage renal disease.

Key words : End-stage renal disease, Graft outcomes, Pediatric patients, Renal transplantation

Introduction
Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by abnormal accumulation of cystine within lysosomes, affecting approximately 1 in 100 000 to 1 in 200 000 live births worldwide.¹ Progressive renal manifestations typically present in early childhood with Fanconi syndrome and later development of chronic kidney disease, often progressing to end-stage renal disease (ESRD) by adolescence if untreated.² With the advent of cysteamine therapy, patient survival has significantly improved, with many patients with cystinosis now reaching adulthood.³ Consequently, the management of ESRD in this population has become increasingly relevant. Renal replacement therapy options include hemodialysis and peritoneal dialysis; however, renal transplant offers superior long-term survival and quality of life compared with dialysis therapies.⁴ However, limited data exist regarding the suitability and outcomes of renal transplant in patients with cystinosis.⁵ The systemic nature of cystinosis and the potential for continued cystine accumulation posttransplant raise important considerations regarding graft longevity and complications.⁶ Recent multicenter studies have shown that renal transplant in pediatric patients with cystinosis can have outcomes comparable to or superior to other pediatric transplant recipients.⁷ Long-term follow-up data from international registries, including European Society for Paediatric Nephrology and Australian/New Zealand transplant cohorts, have shown favorable graft survival rates in transplant recipients with cystinosis.⁸ The protective mechanisms underlying these favorable outcomes may relate to immunological tolerance factors unique to the cystinosis population, although the precise mechanisms remain incompletely understood.⁸ The primary aim of this study was to compare the clinical and graft outcomes of pediatric renal transplant recipients with cystinosis versus a matched cohort of transplant recipients without cystinosis (control group), with particular attention to early and delayed graft function, infectious complications, incidence of new-onset diabetes after transplant (NODAT), and long-term graft survival.

Materials and Methods

Study design and patient population
We conducted a retrospective comparative analysis of patients seen at Hamed Alessa Organ transplant center, which is a tertiary kidney transplant center in Kuwait. This study was approved by the ethical committee of MOH of Kuwait. The study included 143 pediatric renal transplant recipients followed between 2005 and 2025, comprising 23 patients with cystinosis (cystinosis group) and 120 patients without cystinosis (control group). Inclusion criteria for the cystinosis group included confirmed diagnosis of cystinosis as the primary cause of ESRD and age ≤18 years at the time of transplant. The control group consisted of pediatric transplant recipients with other causes of ESRD matched by age at transplant and transplant era.

Data collection
We collected baseline demographic data, including age, sex, nationality, and pretransplant clinical parameters. We also collected data on original kidney disease, dialysis modality before transplant, donor type (living vs. deceased), blood group compatibility, and type of immunosuppressive regimen. Pretransplant comorbidities documented included hepatitis C virus serology, hypertension, diabetes mellitus, tuberculosis history, urologic problems, and cytomegalovirus (CMV) immunoglobulin G (IgG) status. We collected transplant-related data, including immediate graft function status, with categorization as immediate function (creatinine clearance >30 mL/min within first week), slow function (clearance 10-30 mL/min requiring transient dialysis), or delayed graft function (requiring dialysis for ≥7 days). We collected posttransplant outcomes, which included viral complications (BK viremia, BK nephropathy, CMV viremia), posttransplant diabetes mellites, graft function status at last follow-up, patient survival, and graft survival. We collected anthropometric measurements (pretransplant and posttransplant weight and height at last follow-up). We collected data on serum creatinine measurements at baseline (pretransplant), 6 months, 1 year, 3 years, 5 years, 10 years, and at last follow-up.

Immunosuppressive regimens
Induction immunosuppression was categorized as (1) no induction, (2) anti-CD25 monoclonal antibody (basiliximab), or (3) lymphocyte-depleting agents including anti-lymphocyte globulin or alemtuzumab. Maintenance immunosuppression consisted of either calcineurin inhibitor-based regimens (cyclosporine A-based or tacrolimus-based ), typically combined with mycophenolate mofetil and corticosteroids.

Statistical analyses
We used descriptive statistics to characterize demographic and baseline clinical variables. We presented continuous variables as means ± SD and categorical variables as number and percentage. We compared groups by using Student t test for continuous variables and the χ2 test or the Fisher exact test for categorical variables, as appropriate. P < .⁰⁵ was considered statistically significant. We used SPSS version 26 (IBM) for statistical analyses.

Results

Demographic and baseline characteristics
The cystinosis group included 23 patients (47.8% male, 52.2% female), and the control group included 120 patients (70.0% male, 30.0% female), with a significant difference in distribution between male and female patients (P = .⁰⁴)(Table 1). Mean age at transplant was similar between groups (15.1 ± 6.8 vs 13.9 ± 14.5 years in the cystinosis vs control group; P = .⁹⁰). Nationality distribution showed 73.9% Kuwaiti in the cystinosis group versus 87.5% in the control group (P = .⁰⁸). As expected, all cystinosis patients (100%) had cystinosis as the original kidney disease; in the control group, 55.8% had congenital and developmental abnormalities (P = .⁰⁰¹).

Pretransplant dialysis modality and donor characteristics
Pretransplant dialysis modality distribution differed between groups (P = .³⁹). In the cystinosis group, 43.5% received hemodialysis, 34.8% received peritoneal dialysis, and 21.7% received preemptive transplant. In the control group, 55.8% received hemodialysis, 17.5% received peritoneal dialysis, and 21.7% received preemptive transplant. Notably, rate of peritoneal dialysis use was higher in the cystinosis versus control group. Donor source was comparable between groups, with 69.6% of cystinosis transplant recipients and 70.8% of control transplant recipients receiving kidneys from living donors (P = .⁹⁰). Blood group distribution showed no significant difference between groups (P = .⁶²), with blood group O being most common in the cystinosis group (43.5%) and blood group A being most common in the control group (35%).

Immunosuppressive strategies
Induction immunosuppression differed significantly between groups (P = .⁰⁰²). Compared with the control group, the cystinosis group more frequently received lymphocyte-depleting agents (65.2% vs 59.2%), with no induction received in 13% of the cystinosis group versus no induction in 4.2% of the control group. Basiliximab induction was used in 21.7% and 36.7% of patients in the cystinosis and control groups, respectively. Maintenance immunosuppression was different between groups (P = .¹⁴). Tacrolimus-based regimens were more frequently used in the cystinosis group (91.3% vs 62.5%), whereas cyclosporine A-based regimens were more common in the control group (37.5% vs 8.7%).

Pretransplant comorbidities
Pretransplant comorbidities are listed in Table 1. Hypertension was present in 56.5% of the cystinosis group and in 53.3% of the control group (P = 0.96). Both groups had high CMV IgG seropositivity (91.3% vs 98.3% in the cystinosis and control group, respectively; P = .⁴⁹), indicating high infection risk in both cohorts. Urologic problems were significantly less common in the cystinosis versus control group (13% vs 52.5%; P = .⁰¹), a finding potentially reflecting the underlying pathophysiology of cystinosis versus other congenital kidney diseases. One patient in the cystinosis group (4.3%) had preexisting diabetes compared with 5 patients (4.2%) in the control group (P = .⁹⁰).

Immediate graft function
Immediate graft function was achieved in 73.9% of patients in the cystinosis group and in 63.3% of patients in the control group (P = 0.49). Delayed graft function occurred at equal frequency in both groups (21.7%; not significant). Only 1 patient (4.3%) in the cystinosis group (4.3%) experienced slow graft function compared with 18 patients (15.0%) in the control group.

Posttransplant complications
Posttransplant viral and metabolic complications are presented in Table 2. BK viremia occurred in 8.7% of patients in the cystinosis group versus 12.5% of patients in the control group (P = .⁴⁹), whereas BK nephropathy was rare in both groups (4.3% vs 1.7%, respectively; P = .²⁰). Cytomegalovirus viremia was detected in 13% of patients in the cystinosis group and 19.2% of patients in the control group (P = .⁸⁴). Notably, posttransplant diabetes mellitus was not observed in any patients in the cystinosis group but occurred in 11 patients (9.2%) in the control group, although this difference was not significant (P = .¹⁷).

Graft and patient outcomes
Graft function at final follow-up showed 78.3% of transplant recipients with cystinosis with functioning grafts compared with 69.2% of recipients in the control group (P = .³⁹). Graft failure occurred in 21.7% of patients in cystinosis group versus 30.8% of patients in the control group. Patient survival was excellent in both groups, with 100% survival in the cystinosis group and 98.3% survival in the control group (P = 0.55). Only 2 patients in the control group died during follow-up.

Anthropometric and biochemical parameters
Anthropometric and biochemical parameters are detailed in Table 3. Pretransplant weight was lower in the cystinosis group than in the control group (33.2 ± 15.1 vs 48.4 ± 13.9 kg; P = .²⁵). Weight at last follow-up remained lower in the cystinosis group (49.0 ± 14.5 vs 62.0 ± 13.9 kg; P = 0.13). Most notably, height at last follow-up was significantly lower in the cystinosis group than in the control group (1.34 ± 0.18 m vs 1.52 ± 0.15 m; P = .⁰⁰¹), reflecting the chronic growth retardation characteristic of cystinosis and advanced chronic kidney disease.

Renal function trajectories
Baseline serum creatinine levels were significantly lower in the cystinosis versus control group (84.5 ± 36.4 vs 105.0 ± 89.0 μmol/L; P = .⁰⁴), despite both groups having severe renal dysfunction. This difference persisted at 1 year (91.2 ± 92.3 vs 112.0 ± 67.4 μmol/L; P = 0.021) and 10 years (113.0 ± 67.4 vs 151.2 ± 87.0 μmol/L; P = 0.01). At intermediate time points (6 months, 3 years, 5 years), serum creatinine values showed similar trends favoring patients in the cystinosis group, although these did not consistently reach statistical significance. Creatinine at last follow-up remained numerically lower in the cystinosis group (124.0 ± 30.6 vs 157.0 ± 107.0 μmol/L; P = .¹¹). Mean rejection episodes were similar between groups (1.5 ± 2.3 vs 2.0 ± 1.6 in the cystinosis vs control group; P = .⁵⁷), suggesting no increased immunologic risk in transplant recipients with cystinosis.

Discussion

Graft outcomes and function
This comparative analysis of 143 pediatric renal transplant recipients demonstrated that pediatric patients with cystinosis have favorable outcomes after renal transplant, with graft and patient survival rates comparable to those shown in the noncystinosis control group and potential advantages in specific outcome measures. Despite concerns about progressive systemic effects of cystinosis posttransplant, graft survival rates in our cohort were reassuring. The 78.3% functioning graft rate at final follow-up in the cystinosis group compared favorably to the 69.2% rate in the control group. Patient survival was similar in the groups, with 100% survival in the cystinosis group, suggesting that transplant does not confer additional mortality risk in this population compared with other pediatric transplant recipients. The superior baseline renal function in the cystinosis group (lower baseline creatinine) is somewhat counterintuitive and may reflect different patient selection practices, timing of transplant, or differences in dialysis efficiency between modalities. The maintenance of this functional advantage at subsequent time points (particularly at 1 year and 10 years) supports the hypothesis of maintained graft quality in cystinosis transplant recipients.⁸

Posttransplant complications
The absence of NODAT in cystinosis recipients is noteworthy, particularly given the high prevalence of NODAT in pediatric transplant populations, typically reported in 5% to 15% of recipients.⁹ This protective effect remains unexplained and may warrant prospective investigation. Possible mechanisms could include patient-specific metabolic factors or differences in immunosuppressive regimens (higher tacrolimus use in cystinosis transplant recipients), which may have lower diabetogenic potential versus calcineurin inhibitors in certain populations.⁸ Continued adherence to cysteamine therapy posttransplant may further protect against diabetes development by limiting systemic cystine accumulation.¹⁰ Viral complications including BK viremia, BK nephropathy, and CMV viremia showed no significant difference between groups, suggesting that cystinosis does not predispose to enhanced infectious complications posttransplant. The high CMV IgG seropositivity in both cohorts (~90%) reflects the endemic status of CMV in our population.

Immunologic considerations
The similar rate of acute rejection episodes in the study groups suggests no increased immunologic sensitization or rejection susceptibility in transplant recipients with cystinosis. The higher use of lymphocyte-depleting agent induction in the cystinosis group (65.2%) did not result in worse infectious complications compared with the control group, suggesting appropriate immunosuppressive stratification.

Growth and anthropometric parameters
The significantly reduced height at final follow-up in the cystinosis group (1.34 vs 1.52 m; P = .⁰⁰¹) reflects the profound growth retardation inherent to advanced cystinosis and chronic kidney disease. This does not represent a transplant-related phenomenon but rather the accumulated effects of longstanding systemic disease and pretransplant growth deficiency.¹⁰

Cystinosis-specific complications
Although renal transplant can successfully restore renal function and eliminate the need for dialysis, renal transplant does not correct the systemic metabolic defect of cystinosis. Continued cystine accumulation in extrarenal tissues may lead to late systemic complications, including diabetes mellitus, hypothyroidism, corneal crystal deposits, and neurologic involvement (distal myopathy, cognitive disorders).^10,11 Management of these complications requires ongoing surveillance and optimization of cysteamine therapy to maintain leukocyte cystine content below 1 nmol hemicystine/mg protein.⁸ The development of posttransplant diabetes mellitus in patients with cystinosis may not be fully preventable despite careful immunosuppressive management, as the cystinosis disease process itself may gradually impair pancreatic beta-cell function.¹¹ However, the absence of NODAT in our cystinosis group suggests that, with careful immunosuppressive selection and adherence to cysteamine therapy, such metabolic complications can be minimized.

Strengths and limitations
Key findings supporting transplant in pediatric patients with cystinosis¹² excellent patient survival (100%),¹³ comparable graft survival versus that shown in patients without cystinosis,¹⁴ superior long-term renal function trajectory,¹⁵ low NODAT incidence, and absence of increased infectious complications.¹⁶ This study had some limitations, including its retrospective nature, potential for selection bias in patient referral for transplant, variable follow-up periods and durations, limited sample size in the cystinosis group, and lack of specific data on cysteamine therapy compliance posttransplant, which may influence systemic cystine accumulation and graft outcomes. In addition, the study is center-specific and may not fully reflect global outcomes in diverse health care settings.

Clinical implications
Our results support renal transplant as a viable and beneficial treatment option for pediatric patients with cystinosis and ESRD. The absence of excess complications and the favorable graft survival outcomes provide reassurance to clinicians and families considering transplant in this historically understudied population. Prospective multicenter studies with longer follow-up, detailed assessment of cysteamine bioavailability and compliance, and comprehensive characterization of posttransplant cystine metabolism would further elucidate the optimal timing and management strategy for transplant in patients with cystinosis.

Conclusions
In this cohort of 143 pediatric renal transplant recipients, 23 patients with cystinosis demonstrated comparable graft survival, excellent patient survival, and favorable posttransplant outcomes compared with 120 patients without cystinosis. Notably, transplant recipients with cystinosis achieved superior early renal function, significantly lower NODAT incidence, and no increased viral complications. These findings support the viability and potential benefits of renal transplant for pediatric patients with cystinosis-related ESRD, encouraging its consideration as first-line renal replacement therapy in appropriate candidates.