Objectives: Joubert syndrome is a rare ciliopathy in which kidney disease can quietly progress to end-stage kidney disease, often in children and young adults. For these patients and their families, kidney transplant is a turning point, yet published experience remains limited. Here, we share our center’s experience with kidney transplant in 5 patients with Joubert syndrome who progressed to end-stage kidney disease, highlighting medical outcomes and practical challenges.
Materials and Methods: We conducted a retrospective case series of 5 patients with Joubert syndrome and end-stage kidney disease who received kidney transplants at our center. We reviewed medical records for demographic data, neurological and extrarenal features, renal course, transplant details, immunosuppression, complications, and long-term graft and patient outcomes.
Results: The cohort included 3 male and 2 female patients who received transplants between 12 and 40 years of age. Two patients had genetically confirmed Joubert syndrome, and 3 patients had a clinical diagnosis. Nephronophthisis was the documented cause of end-stage kidney disease in 2 children, whereas 3 patients had end-stage kidney disease attributed to Joubert syndrome without further histology classification. All patients received calcineurin inhibitor-based triple immunosuppression. Delayed graft function occurred in all 5 recipients. Two patients developed biopsy-proven T-cell-mediated acute rejection, successfully treated with pulse steroids. At last follow-up, 3 patients were alive with functional grafts, 1 patient was alive on dialysis after graft loss due to chronic pyelonephritis, and 1 patient died from severe infection with a functional graft.
Conclusions: Kidney transplant is feasible and generally effective in patients with Joubert syndrome, offering durable renal replacement in most cases. However, the universal occurrence of delayed graft function and the effect of infectious complications, which led to 1 graft loss and 1 death, emphasize the need for careful perioperative management, urological assessment, and close long-term follow-up within a multidisciplinary framework.

Key words : Delayed graft function, Kidney transplantation, Outcome, Perioperative management

Introduction
Joubert syndrome (JS) is mainly an autosomal recessive ciliopathy characterized by a specific malformation of the cerebellum and brainstem seen on cranial magnetic resonance imaging, known as the molar tooth sign, which resembles the cross-section of a tooth on axial images. The 3 main diagnostic criteria for JS include the presence of the molar tooth sign, hypotonia in infancy that later progresses to ataxia, and developmental delay or intellectual disability. In addition, several variable features may be present, such as breathing abnormalities (which often manifest as episodic tachypnea and/or apnea, particularly during infancy) and abnormal eye movements (most commonly oculomotor apraxia or difficulty initiating voluntary saccades).¹ The first gene associated with JS, NPHP¹, was identified in 2004, and was a landmark to understand the genetic basis of the disorder. Since then, more than 30 genes have been linked to JS. However, most of these genes account for fewer than 10% of cases individually, and some associations are supported by only a very few patients. This highlights the genetic heterogeneity of JS, for which multiple distinct genetic defects can lead to a similar clinical and radiological phenotype.² Despite the diversity of genes involved, a unifying feature is that all identified JS genes are related to the primary cilium, which is a small, antenna-like cellular structure. Specifically, many of these genes function at the transition zone of the cilium, the region at which the cilium connects to the plasma membrane. This transition zone acts as a gatekeeper to control which proteins enter or exit the cilium, and this zone is critical for maintenance of ciliary structure and signaling function. Disruption of these genes can therefore compromise ciliary assembly and signaling, leading to the multisystem features seen in JS.³ The primary cilium is present on nearly all cell types and plays a central role in development and cellular signaling. The primary cilium helps cells establish left-right body symmetry during embryogenesis, transduce environmental signals, and coordinate essential intracellular pathways, including Sonic Hedgehog signaling, which is vital for tissue patterning and organogenesis. Dysfunction of ciliary proteins in JS therefore affects a wide range of organ systems, explaining the neurological, respiratory, and ocular manifestations commonly observed in affected patients.⁴ Kidney involvement is a common complication in JS and affects approximately 25% to 30% of patients. In a recent cohort study of 97 individuals with JS, 29 patients (30%) exhibited renal abnormalities. The most frequent phenotype was nephronophthisis (NPH), observed in 20% of cases, followed by unilateral cystic dysplastic kidneys in 3% of cases, and undetermined cystic kidney disease in 7% of cases. Most of these renal abnormalities were initially identified via ultrasonography imaging, but only 18 of the 29 affected individuals (62%) had a confirmed diagnosis of chronic kidney disease (CKD). This highlights the variable penetrance of renal manifestations in JS and emphasizes the importance of systematic kidney evaluation in this patient population.⁵ Nephronophthisis is a distinct clinicopathological entity characterized by progressive disruption of the renal tubular basement membranes, tubular atrophy, interstitial fibrosis, and the development of small corticomedullary cysts, typically in kidneys that are small or typical in size. In most patients, NPH remains asymptomatic or minimally symptomatic during the first decade of life. Early manifestations may include polyuria, polydipsia, and mild anemia, which are often nonspecific and easily overlooked. Despite this slow initial progression, NPH inevitably advances during adolescence or early adulthood, leading to progressive CKD and ultimately end-stage renal disease (ESKD, ie, stage 5 CKD). Renal failure represents a significant cause of morbidity and mortality in JS, and management through dialysis or renal transplant can be complicated by the presence of severe neurological or systemic comorbidities.⁶ Early detection of renal disease in JS remains a major clinical challenge. Most patients are diagnosed with JS in infancy or early childhood due to prominent neurological features, when kidney function remains at reference levels. Identification of patients at risk for progressive renal disease is therefore crucial for timely intervention. Although kidney ultrasonography is a useful tool for detection of cystic kidney diseases, its sensitivity is limited in cases of isolated NPH. Ultrasonography may reveal increased echogenicity or small corticomedullary cysts, but in some patients the findings are subtle or even absent. Furthermore, ultrasonography is an operator-dependent method and cannot reliably predict which patients will develop progressive CKD.⁷ There is presently no early quantitative biomarker for renal insufficiency in JS. The absence of reliable predictive tests hinders proactive monitoring and management of at-risk individuals. Given the potential severity of renal involvement and its effect on long-term outcomes, development of sensitive and specific biomarkers for early kidney dysfunction in JS is an important unmet need. Such tools would enable clinicians to stratify patients according to risk, optimize surveillance schedules, and initiate timely interventions to inhibit disease progression, ultimately improving survival and quality of life for affected individuals.⁸ Kidney transplant is a feasible and effective treatment for patients with JS who develop end-stage kidney disease (ESKD), most commonly due to NPH. Although data are limited, previously published reports have described transplant recipients with JS who have demonstrated satisfactory graft function, with most grafts remaining stable during follow-up periods of 2 to 3 years and with outcomes comparable with other pediatric kidney transplant populations. Standard immunosuppression regimens, including calcineurin inhibitors, steroids, and mycophenolate, are generally well tolerated, and acute rejection episodes are uncommon and treatable. Careful pretransplant evaluation is essential, as comorbidities such as neurological impairment, hydrocephalus with shunting, or liver disease can increase surgical and postoperative risks. Observational studies of juvenile NPH, the main renal pathology in JS, further support excellent long-term transplant outcomes, establishing kidney transplant as a viable option for improvement of survival and quality of life in affected individuals.⁹ However, the published data on kidney transplant in patients with JS remain sparse. Most reports have focused on the natural history of renal involvement or have described small groups of patients treated with dialysis and transplant. Against this background, each transplant case provides not only clinical information but also insight into how JS patients and their care teams navigate complex choices with regard to timing, risk, and long-term expectations. Here, we present our single-center experience of 5 patients with JS who underwent kidney transplant. We describe these patients and their progress to ESKD, their transplant scenarios, and their follow-ups. We also place our experience in the context of the existing literature and reflect on our improved knowledge regarding care and treatment for people with JS.

Materials and Methods

Study design
We conducted a retrospective case series of patients with JS who developed ESKD and received kidney transplants at our center. Because of the rarity of JS, the design of our study allowed us to capture all relevant experience for an extended period.

Ethical considerations
This study was conducted in accordance with institutional and international ethical standards. Informed consent for inclusion and use of anonymized data was obtained from all patients or their legal guardians. Throughout data collection and analysis, we ensured strict confidentiality of patient information.

Patient identification
We screened our transplant database for patients with a diagnosis of JS based on clinical features and/or neuroimaging data, with or without genetic confirmation; with documented progression to ESKD requiring renal replacement therapy; and with subsequent kidney transplant at our center. For each identified patient, we reviewed full medical records.

Data collection
Data were abstracted into the following predefined categories. Demographic information included age at JS diagnosis (where available) and age at transplant, sex, family history of JS, and (when documented) consanguinity. Neurological and extrarenal features included presence or absence of hypotonia, ataxia, developmental delay or intellectual disability, abnormal eye movements, breathing abnormalities, and brain magnetic resonance imaging findings including the molar tooth sign. Documentation of ocular, hepatic, or other organ involvement was also recorded. Renal course included type of renal involvement (eg, NPH, cystic kidney disease, or ESKD of presumed JS origin), age at onset of renal manifestations; clinical signs such as polyuria, polydipsia, and anemia; laboratory data, imaging findings, and progression from CKD to ESKD. Transplant-related data included donor type (living related donor or deceased donor), induction immunosuppression, maintenance regimen, perioperative complications, delayed graft function (DGF), biopsy-proven acute rejection episodes, major infections when documented, and the duration of posttransplant follow-up. Outcomes included graft function (as measured by serum creatinine and estimated glomerular filtration rate at last follow-up), graft status (functional vs failed), patient survival, and cause of death when applicable.

Definitions
We defined DGF as the requirement for dialysis within the first week after transplant. We defined acute rejection as biopsy-proven T-cell-mediated rejection treated according to standard protocols. We defined graft loss as return to permanent dialysis or graft nephrectomy, regardless of residual function. Given the small sample size, we focused on descriptive reporting rather than formal statistical testing.

Results
Five patients (3 male, 2 female) with JS and ESKD underwent kidney transplant at our center, and age at transplant ranged from 12 to 40 years old. Two patients (case 1 and case 3) had genetically confirmed JS, whereas 3 patients had a clinical diagnosis of JS based on characteristic features and/or imaging but without molecular confirmation. The spectrum of neurological involvement was milder than the typical expectation for JS. Three patients had no documented neurological manifestations at the time of transplant, and in 2 patients the presence of neurological features was noted but not severe enough to impede daily functioning or informed consent. None had documented extrarenal involvement such as hepatic or ocular disease in the pretransplant evaluation. Nephronophthisis was clearly documented in 2 patients (both of whom were adolescent patients), whereas the remaining 3 patients had ESKD labeled simply as “ESKD” in the context of JS, reflecting long-standing CKD likely of tubulointerstitial or cystic nature. Baseline clinical information is summarized in Table 1. Two patients received kidneys from living related donors (case 1 and case 3), whereas 3 patients received organs from deceased donors (case 2, case 4, and case 5). Induction immunosuppression consisted of anti-thymocyte globulin in 4 patients and basiliximab in 1 patient (case 5). All patients were maintained on a standard triple regimen of tacrolimus, mycophenolate mofetil, and prednisolone. One consistent theme across all 5 cases was the challenge of early graft function. All 5 patients experienced DGF that required dialysis in the first posttransplant week. For the patients and their families, this period of DGF was often the most stressful, as the promise of transplant initially appeared uncertain. Two patients (case 1 and case 3) developed biopsy-proven T-cell-mediated acute rejection during follow-up. In both of these cases, the rejection episodes were managed with high-dose pulse steroids and resolved without permanent loss of graft function. These transplant details are summarized in Table 2. Follow-up ranged from 6 months in the most recent transplant to 11 years in our longest survivor. Outcomes are summarized in Table 3.

Case 1: a 40-year-old male patient with genetically confirmed Joubert syndrome
In case 1, after a living related transplant and an initial period of DGF, the patient experienced an episode of T-cell-mediated rejection successfully treated with steroids. At 6 months, he demonstrated stable graft function with a serum creatinine of 141 μmol/L and was living independently with good quality of life.

Case 2: a 12-year-old female patient with nephronophthisis
In case 2, the patient received a deceased donor graft after a period on peritoneal dialysis. Her early posttransplant course was marked by DGF but no acute rejection. After more than 8 years of follow-up, she developed chronic allograft dysfunction. Ultimately, the graft failed due to chronic pyelonephritis, and she returned to dialysis after 102 months. She remained alive and engaged in ongoing care.

Case 3: a 16-year-old male patient with genetically confirmed Joubert syndrome
In case 3, after a living related transplant and DGF, the patient experienced 1 episode of T-cell-mediated rejection that responded to pulse steroids. At 60 months of follow-up, he remained alive with a functional graft and mildly impaired kidney function (serum creatinine 171 μmol/L), attending school and daily activities.

Case 4: a 25-year-old male patient with clinically diagnosed Joubert syndrome
In case 4, the patient received a deceased donor transplant and experienced DGF but no rejection episodes. Remarkably, at 132 months of follow-up, his graft function remained excellent, with a serum creatinine of 96 μmol/L. He was living with a stable transplant more than a decade after surgery.

Case 5: a 13-year-old female patient with nephronophthisis
In case 5, the patient’s course of treatment demonstrated the vulnerability of JS patients to infection. She received a deceased donor kidney with basiliximab induction and had DGF but no rejection. During follow-up, however, she developed a severe infectious complication and died 36 months after transplant. At the time of her death, the graft remained functional, with a serum creatinine of 161 μmol/L.

Discussion
In JS, neurological signs often trigger the first specialist referrals. Yet, as our cases show, kidney disease can quietly shape the long-term story. Two of our patients, both children, developed ESKD due to NPH, echoing the dominant renal phenotype seen in larger cohorts. Other patients in our cohort developed ESKD at older ages, including 1 male patient who received a transplant at 40 years, which extends beyond the typical age range reported in prospective series. This variability should remind clinicians that JS is not a single well-defined pathway but is a condition that lies on a spectrum by which some individuals with relatively mild neurological features may remain undiagnosed until kidney failure brings them into nephrology care.^10-12 Only 2 of our 5 patients had molecular confirmation of JS. Genetic testing has been shown as invaluable in clarifying diagnosis, anticipating extrarenal complications, and enabling informed family counseling. In everyday clinical practice, however, access to comprehensive genetic testing may be constrained by high financial cost, lack of availability, or inopportune timing.^11,13,14 Our experience supports efforts to integrate genetic evaluation into the pretransplant workup for patients with suspected JS or other ciliopathies whenever possible and also shows that important clinical decisions, including transplant, often must proceed even when genetic data are incomplete. Our series adds to the growing (but modest) body of literature suggesting that kidney transplant is a feasible and generally successful option for patients with JS.^15,16 Most of our patients achieved good medium-term to long-term graft function, and 3 patients remained alive with functional grafts at last follow-up, including 1 patient who survived more than a decade after transplant. All 5 patients required dialysis in the first week after transplant. Although this may partly reflect donor factors and center practices, it highlights the importance of careful perioperative hemodynamic management, early surveillance for ischemia-reperfusion injury, and thoughtful communication with families during this unstable period.^17-19 Two patients experienced T-cell-mediated rejection, and both patients were successfully treated with steroids. This scenario aligns with experiences that have been reported from other pediatric and young adult transplant populations, suggesting that JS itself does not necessarily confer a unique immunological risk and that vigilance remains essential.^20,21 One patient experienced graft loss due to chronic pyelonephritis after many years, and 1 patient died from severe infection with a functional graft. Although detailed urology and microbiology data were incomplete, these events strongly suggest that urinary tract and systemic infections are key determinants of long-term outcome in this group.^22,23 These observations complement previously published reports that have shown general favorable graft survival in JS but also highlight that complications may emerge late and are often modifiable. These observations support a structured approach to pretransplant evaluation, including bladder and urinary tract assessment, and to posttransplant surveillance tailored in response to local infection patterns and individual risk.^24,25 Although overt extrarenal manifestations were limited in our small cohort, JS and related ciliopathies frequently involve the retina, liver, endocrine system, and central nervous system. Cases described elsewhere have shown that successful kidney transplant can improve not only renal function but also growth, anemia, and functional independence, especially when combined with rehabilitation and multidisciplinary follow-up.^26-28 A truly multidisciplinary model (ie, a model that integrates nephrology, neurology, ophthalmology, hepatology, genetics, endocrinology, rehabilitation, psychology, and social work) can help translate technical transplant success into a meaningful, persistent benefit.

Limitations
Our experience must be interpreted with several limitations. The series was small and was from a single center, so we cannot precisely define rates of complications or outcomes. Retrospective data collection meant that some details, particularly around neurological examinations, urological anatomy, and infection histories, were incomplete. Genetic testing was not available for all patients, limiting genotype-phenotype analyses. Finally, without a control group of non-JS transplant recipients, we cannot fully quantify the degree to which JS contributed to specific risks such as DGF or infection.

Conclusions
For patients with JS who develop ESKD, kidney transplant can offer many years of improved health and, in some cases, a stable long-term graft. Our experience with 5 such patients shows that transplant is not only technically feasible but, in most cases, clinically rewarding. However, the universal occurrence of DGF, the occurrence of chronic pyelonephritis leading to graft loss, and 1 infection-related death are 3 reminders of the vulnerability of these patients. Carefully planned perioperative care, systematic urological assessment, tailored infection prophylaxis, and truly multidisciplinary follow-up are essential to convert surgical success into a durable, comprehensive benefit for the patient.