Addressing the psychosocial aspects of transition to adult care in patients with cystinosis.

Cystinosis is a rare autosomal-recessive lysosomal storage disease that progressively affects multiple organs beginning with the kidneys. Patients require lifelong multidisciplinary care for the management of kidney disease and progressive extra-renal manifestations, and thus, they are especially fragile and vulnerable during transition from pediatric to adult care. Previous documents have provided guidance to help the medical transition of these highly burdened patients. Patients and their families often experience great psychological distress and face significant social challenges; for these reasons, they often need help from psychologists, social workers, and other psychosocial professionals. Due to the rarity of the disease, most psychosocial professionals have no expertise in this disorder and require advice. To this end, a steering committee (SC) composed of six experts, including pediatric nephrologists, psychologists, and social workers with experience in the care for patients with cystinosis, have identified and addressed seven key questions related to psychosocial challenges of the disease and the burden of treatment. Ten additional international experts (the extended faculty, EF) were invited to answer these questions. Since robust evidence is lacking, as in many rare diseases, conclusions were based on collective agreement between members of the SC and the EF, and the consolidated answers were summarized into expert opinion statements. The present document contains information on the concerns and psychosocial burden of patients with cystinosis and of their caregivers, and provides practical advice for timely and appropriate support to facilitate the transition to adult care.

X-linked hypophosphatemia: The value of feedback focus groups to assess patient and caregiver needs.

X-linked hypophosphatemia (XLH) is a rare, multi-systemic, invalidating disease requiring a multi-disciplinary approach. No specific action in XLH, neither for the patients' specific needs nor for the methodology for the evaluation of these were found. Thus, to identify the needs of XLH patients and their caregivers, we organised focus groups in our reference centre with a view to build educational sessions. Focus groups including either XLH children, XLH adults, or caregivers ran in parallel. Each group was led by a person trained in therapeutic education (nurse, paediatric nephrologist) with another healthcare provider specialised in XLH (rheumatologist, nephrologist). One additional person with knowledge of XLH (clinical research associate, paediatric resident) took minutes. The duration of each session was 1.5h; XLH patients/caregivers were asked to answer age-adapted "open questions" on their daily life and quality of life. At the end, a global restitution was made. The needs identified were later grouped and analysed, which allowed us to build the educational sessions. The XLH children group included 5 children, the XLH adults group included 10 adults, and the caregivers group included 6 parents or partners. Major needs were identified: knowledge of XLH, treatment, dental care and adapted physical activity, with additional questions on socio-professional adaptations and financial support in adults. Partner patients were also identified to co-build the support programme. The study allowed us to identify the needs of XLH patients and their caregivers using the focus group method and then, using these needs, to build educational sessions and a therapeutic education programme for XLH patients.

Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective.

BACKGROUND: Nephropathic cystinosis (NC) is a rare lysosomal disease, leading to early kidney failure and extra-renal comorbidities. Its prognosis strongly relies on early diagnosis and treatment by cysteamine. Developing economies (DEing) face many challenges when treating patients for rare and chronic diseases. The aim here is to evaluate the access to investigations and treatment in DEing, and to assess for potential inequalities with Developed Economies (DEed). METHODS: In this international cross-sectional study, a questionnaire on access, price and reimbursement of genetic, biological analyses, and treatment was sent to nephrology centers worldwide during 2022. RESULTS: A total of 109 centers responded, coming from 49 countries and managing 741 patients: 43 centers from 30 DEing and Economies in transition (TrE), and 66 from 19 DEed. In 2022, genetics availability was 63% in DEing and 100% in DEed, whereas intra leukocytes cystine levels (IL-CL) were available for 30% of DEing patients, and 94% of DEed patients, both increasing over the last decade, as has access to immediate release cysteamine and to cysteamine eye drops in DEing. However, delayed released cysteamine can be delivered to only 7% vs. 74% of patients from DEing and DEed, respectively, and is still poorly reimbursed in DEing. CONCLUSIONS: Over the last decade, access to investigations (namely genetics and IL-CL) and to cysteamine have improved in DEing and TrE. However, discrepancies remain with DEed: access to delayed released cysteamine is limited, and reimbursement is still profoundly insufficient, therefore limiting their current use.

Bone mineral density and growth changes in patients with distal renal tubular acidosis after two-years treatment with a new alkalizing drug (ADV7103) / Cambios en la densidad mineral ósea y en el crecimiento en pacientes con acidosis tubular renal distal tras dos años de tratamiento con un nuevo fármaco alcalinizante (ADV7103)

Background and objectives: ADV7103 is a new prolonged-release treatment for distal renal tubular acidosis (dRTA), containing potassium citrate and potassium bicarbonate. Since acidosis may affect bone mineral contents, the effects of ADV7103 on bone mineral density (BMD) and growth in patients with dRTA over 24 months were evaluated. Patients and methods: Thirty patients (24 paediatric patients and 6 adults) were included in an open-label extension study after a phase II/III trial. BMD, measured by densitometry, was assessed at baseline and at 24 months. Growth was evaluated throughout the study. Plasma bicarbonate, parathyroid hormone, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, bone alkaline phosphatase, calciuria and citraturia, were also determined. Safety and treatment compliance were evaluated as well. Results: After 24 months of treatment with ADV7103, mean spine BMD z-score values significantly increased as compared with baseline (p=0.024). In adults, spine and whole-body densitometry z-scores showed a significant correlation with plasma bicarbonate levels (rS=0.82 and rS=0.97, respectively, p<0.005). There was an increase>0.5 units in z-scores for height and weight in 18% and 36% of the paediatric patients, respectively. With treatment, plasma bicarbonate concentration and calciuria at the different visits were normal in 69–86% and 93–96% patients, respectively. Only nine treatment-related gastrointestinal AEs of mild/moderate severity, were reported in five patients. Conclusions: Two years of ADV7103 treatment improved growth and increased spine BMD. These results suggest that control of acidosis by ADV7103 treatment improves bone parameters. (AU)

Antecedentes y objetivo: El ADV7103 es un nuevo tratamiento de liberación prolongada para la acidosis tubular renal distal (ATRd), que contiene citrato potásico y bicarbonato potásico. Dado que la acidosis puede afectar al contenido mineral óseo, se ha evaluado el efecto de dicho medicamento a lo largo de 24 meses sobre la densidad mineral ósea (DMO) y el crecimiento en pacientes con ATRd. Pacientes y métodos: Se incluyeron treinta pacientes (24 pediátricos y seis adultos) en un estudio abierto de extensión tras un ensayo clínico de fase II/III. La DMO medida por densitometría se midió al inicio del estudio y los 24 meses. El crecimiento se evaluó a lo largo del estudio. Adicionalmente, se determinaron el bicarbonato plasmático, la parathormona, 25 hidroxivitamina D, 1,25 dihidroxivitamina D, fosfatasa alcalina ósea, calciuria y citraturia. La seguridad y el cumplimento terapéutico también fueron evaluados. Resultados: Tras 24 meses de tratamiento con ADV7103 la media del z-score de DMO de columna aumentó significativamente frente al valor basal (p = 0,024). En los adultos el z-score de la densitometría de columna y corporal total mostró una correlación significativa con los valores de bicarbonato plasmático (rS = 0,82 y rS = 0,97, respectivamente, p < 0,005). Se registró un incremento > 0,5 unidades de z-score para altura y peso en el 18 y 36%, respectivamente, de los pacientes pediátricos. Con el tratamiento, la concentración plasmática de bicarbonato y la calciuria fueron normales en las diferentes visitas en un 69-86% y un 93-96% de los pacientes, respectivamente. Solamente se notificaron nueve eventos adversos gastrointestinales relacionados con el tratamiento, todos de intensidad leve/moderada en cinco pacientes. Conclusiones: Dos años de tratamiento con ADV7103 mejoraron el crecimiento y la DMO de columna. Estos resultados sugieren que el control de la acidosis con dicho tratamiento provoca una mejora de parámetros óseos. (AU)

Young XLH Patients-Reported Experience with a Supportive Care Program.

Purpose: X-linked hypophosphatemia (XLH) is a rare, chronic, genetic condition characterized by renal phosphate wasting and abnormal bone and teeth mineralization. It represents a challenging and multifaceted disease that causes wide-ranging impacts on patients' lives. In this context, a scientific committee has designed a support initiative for patients treated for XLH: the aXess program. We sought to determine if a patient support program (PSP) could help XLH patients cope with their condition. Methods: During the 12 months of participation in the aXess program, XLH patients were contacted by phone by a nurse to coordinate their treatment, ensure treatment adherence, and provide motivational interviews. A Pediatric QOL inventory was conducted on all participants at enrollment (D0), at month 6, and month 12. Results: Altogether, a total of 59 patients were enrolled in the program. Most patients reported an improvement in QOL in all examined dimensions by month 12 (physical, emotional, social, and school, 85.4 ± 0.2 at month 12 versus 75.6 ± 0.3 at enrollment, p<0.05). Patients were very satisfied with the program, with a mean overall satisfaction score of 9.8 ± 0.6 (on a scale from 0 to 10) at month 6 and 9.2 ± 1.5 at month 12. Conclusion: Our findings indicate that this program might improve the QOL for patients with chronic conditions such as XLH through patient education, therapy adherence, motivational interviews, and frequent follow-up. It links the home environment and overall illness management, bringing patients, families, and caregivers together.

Hydration and Nephrolithiasis in Pediatric Populations: Specificities and Current Recommendations.

Renal lithiasis is less frequent in children than in adults; in pediatrics, lithiasis may be caused by genetic abnormalities, infections, and complex uropathies, but the association of urological and metabolic abnormalities is not uncommon. The aim of this study is to provide a synthesis of nephrolithiasis in children and to emphasize the role of hydration in its treatment. As an etiology is reported in 50% of cases, with a genetic origin in 10 to 20%, it is proposed to systematically perform a complete metabolic assessment after the first stone in a child. Recent data in the field reported increased incidence of pediatric urolithiasis notably for calcium oxalate stones. These changes in the epidemiology of stone components may be attributable to metabolic and environmental factors, where hydration seems to play a crucial role. In case of pediatric urolithiasis, whatever its cause, it is of utmost importance to increase water intake around 2 to 3 L/m2 per day on average. The objective is to obtain a urine density less than 1010 on a dipstick or below 300 mOsm/L, especially with the first morning urine. Some genetic diseases may even require a more active 24 h over-hydration, e.g., primary hyperoxaluria and cystinuria; in such cases naso-gastric tubes or G-tubes may be proposed. Tap water is adapted for children with urolithiasis, with limited ecological impact and low economical cost. For children with low calcium intake, the use of calcium-rich mineral waters may be discussed in some peculiar cases, even in case of urolithiasis. In contrast, sugar-sweetened beverages are not recommended. In conclusion, even if parents and patients sometimes have the feeling that physicians do not propose "fancy" therapeutic drugs, hydration and nutrition remain cornerstones of the management of pediatric urolithiasis.

Bone mineral density and growth changes in patients with distal renal tubular acidosis after two-years treatment with a new alkalizing drug (ADV7103).

BACKGROUND AND OBJECTIVES: ADV7103 is a new prolonged-release treatment for distal renal tubular acidosis (dRTA), containing potassium citrate and potassium bicarbonate. Since acidosis may affect bone mineral contents, the effects of ADV7103 on bone mineral density (BMD) and growth in patients with dRTA over 24 months were evaluated. PATIENTS AND METHODS: Thirty patients (24 paediatric patients and 6 adults) were included in an open-label extension study after a phase II/III trial. BMD, measured by densitometry, was assessed at baseline and at 24 months. Growth was evaluated throughout the study. Plasma bicarbonate, parathyroid hormone, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, bone alkaline phosphatase, calciuria and citraturia, were also determined. Safety and treatment compliance were evaluated as well. RESULTS: After 24 months of treatment with ADV7103, mean spine BMD z-score values significantly increased as compared with baseline (p=0.024). In adults, spine and whole-body densitometry z-scores showed a significant correlation with plasma bicarbonate levels (rS=0.82 and rS=0.97, respectively, p<0.005). There was an increase>0.5 units in z-scores for height and weight in 18% and 36% of the paediatric patients, respectively. With treatment, plasma bicarbonate concentration and calciuria at the different visits were normal in 69-86% and 93-96% patients, respectively. Only nine treatment-related gastrointestinal AEs of mild/moderate severity, were reported in five patients. CONCLUSIONS: Two years of ADV7103 treatment improved growth and increased spine BMD. These results suggest that control of acidosis by ADV7103 treatment improves bone parameters.

Clinical and genetic characteristics of Dent's disease type 1 in Europe.

BACKGROUND: Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis-nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. METHODS: A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. RESULTS: A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. CONCLUSIONS: Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.

X-linked hypophosphatemia, obesity and arterial hypertension: data from the XLH21 study.

BACKGROUND: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate-lipid metabolism, could be involved. METHODS: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min-max)). RESULTS: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4-99) in SOC, 47 (9-98) in burosumab, and 28 (1-94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate-lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab). CONCLUSION: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018-2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information.

X-Linked Hypophosphatemia, Not Only a Skeletal Disease But Also a Chronic Inflammatory State.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare genetic disease caused by a primary excess of fibroblast growth factor 23 (FGF23). FGF23 has been associated with inflammation and impaired osteoclastogenesis, but these pathways have not been investigated in XLH. OBJECTIVE: This work aimed to evaluate whether XLH patients display peculiar inflammatory profile and increased osteoclastic activity. METHODS: We performed a prospective, multicenter, cross-sectional study analyzing transcript expression of 8 inflammatory markers (Il6, Il8, Il1ß, CXCL1, CCL2, CXCR3, Il1R, Il6R) by real-time quantitative polymerase chain reaction on peripheral blood mononuclear cells (PBMCs) purified from total blood samples extracted from patients and healthy control individuals. The effect of native/active vitamin D on osteoclast formation was also assessed in vitro from XLH patients' PBMCs. RESULTS: In total, 28 XLH patients (17 children, among them 6 undergoing standard of care [SOC] and 11 burosumab therapy) and 19 controls were enrolled. Expression of most inflammatory markers was significantly increased in PBMCs from XLH patients compared to controls. No differences were observed between the burosumab and SOC subgroups. Osteoclast formation was significantly impaired in XLH patients. XLH mature osteoclasts displayed higher levels of inflammatory markers, being however lower in cells derived from the burosumab subgroup (as opposed to SOC). CONCLUSION: We describe for the first time a peculiar inflammatory profile in XLH. Since XLH patients have a propensity to develop arterial hypertension, obesity, and enthesopathies, and because inflammation can worsen these clinical outcomes, we hypothesize that inflammation may play a critical role in these extraskeletal complications of XLH.

Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis.

Introduction: Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function. Methods: Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry (n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases (n = 60), and a literature search (n = 218). Results: A total of 383 individuals were available for analysis: 116 NPHP1, 101 NPHP3, 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3-12.0); NPHP1, 13.5 years (interquartile range 10.5-16.5); NPHP4, 16.0 years (interquartile range 11.0-25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7-28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4. Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline. Conclusion: The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling.

Fluconazole in hypercalciuric patients with increased 1,25(OH)2D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial.

BACKGROUND: Hypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels. METHODS: The FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double-blind trial. A total of 60 patients (10-60 years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/day), increased 1,25(OH)2D levels (> 150 pmol/L), and 25-OH-D levels >20 nmol/L will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-h calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-h calciuria in patients who still display at W16 a 24-h hypercalciuria. DISCUSSION: The current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the "off-label" use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04495608 . Registered on July 23, 2020.

Lived experiences of patients with distal renal tubular acidosis treated with ADV7103 and of their caregivers: a qualitative study.

BACKGROUND: Consequences of distal renal tubular acidosis (dRTA) on growth, bone and kidney, sometimes associated with hearing loss, may significantly affect quality of life (QoL). This descriptive qualitative study explores QoL linked to dRTA and gathers the impressions of patients with this rare disease (and caregivers) 5 years after enrolment in a clinical study, during which patients were treated with ADV7103, a prolonged-release granule formulation combining potassium citrate and potassium bicarbonate. Semi-structured, one-hour interviews with 6 adult and 13 paediatric patients with a confirmed diagnosis of dRTA and with parents of paediatric patients were performed using an interview guide. Qualitative analysis of anonymized interview transcripts based on grounded theory was conducted. RESULTS: The main QoL domains impacted by dRTA and its treatment were education/work, social/family life, and emotional and physical well-being. ADV7103 (administered twice daily) was compared with the standard of care (SoC) taken before study entry (more than twice daily). Patients/parents reported that switching from previous SoC to ADV7103 had changed their lives: Difficulties at school due to burdensome administrative issues and need to explain disease and treatment affecting all families of paediatric patients (n = 13) disappeared, facilitating parents who had stopped working (to deal with their child's treatment) to return to work, Family functioning was improved (n = 18), as travel and holidays became easier to organise and patients/parents stopped thinking about managing treatment daily/nightly, reducing tension in the family or couple, The emotional burden of disease perceived was relieved (n = 12) in the absence of treatment-related invasive questions from others, Gastro-intestinal adverse events and taste problems improved with ADV7103 (n = 18) and better compliance led to milder physical impacts and less need to be hospitalised. The mean satisfaction score with ADV7103 compared to SoC was 9 out of 10 (10 = very satisfied). ADV7103 exceeded or met the expectations of 14 out of 17 patients that commented on that. CONCLUSIONS: Qualitative interviews show that dRTA and its treatment have a significant impact on QoL of patients and parents and that ADV7103 helps improve daily-life and reduces treatment burden, resulting in greater overall satisfaction of the patients and their families. Trial registration EU Clinical Trials Register, EudraCT 2013-003828-36 on the 3rd of September 2013.

Intermittent Bi-Daily Sub-cutaneous Teriparatide Administration in Children With Hypoparathyroidism: A Single-Center Experience.

Introduction: The use of teriparatide has been reported in children with hypoparathyroidism as an investigational physiologic replacement therapy. Methods: We aimed to retrospectively report our pediatric experience of bi-daily sub-cutaneous teriparatide. Results are presented as median (25th-75th quartile). As part of the routine follow-up of these patients with hypoparathyroidism, total calcium at H0 (i.e., just before injection) and H4 (i.e., 4 h after teriparatide injection) and other biomarker parameters were regularly assessed. Results: At a median age of 10.7 (8.1-12.6) years, an estimated glomerular filtration rate (eGFR) of 110 (95-118) mL/min/1.73 m2, calcium levels of 1.87 (1.81-1.96) mmol/L and an age-standardized phosphate of 3.8 (2.5-4.9) SDS, teriparatide therapy was introduced in 10 patients at the dose of 1.1 (0.7-1.5) µg/kg/day (20 µg twice daily), with further adjustment depending on calcium levels. Six patients already displayed nephrocalcinosis. Severe side effects were reported in one child: two episodes of symptomatic hypocalcemia and one of iatrogenic hypercalcemia; one teenager displayed dysgueusia. Calcium levels at H0 did not significantly increase whilst calcium at H4 and phosphate levels significantly increased and decreased, respectively. After 12 months, eGFR, calcium and age-standardized phosphate levels were 108 (90-122) mL/min/1.73 m2, 2.36 (2.23-2.48) mmol/L, 0.5 (-0.1 to 1.5), and 68 (63-74) nmol/L, respectively, with a significant decrease in phosphate levels (p = 0.01). Urinary calcium and calcium/creatinine ratio remained stable; no nephrolithiasis was observed but two moderate nephrocalcinosis appeared. Conclusion: Intermittent teriparatide therapy significantly improves calcium and phosphate control, without increasing calciuria. It appears to be safe and well-tolerated in children.

Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation.

Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2-61) years, and a eGFR of 64 (23-149) mL/min/1.73 m2. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.

An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis.

Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.

Composition of urinary stones in children: clinical and metabolic determinants in a French tertiary care center.

As the epidemiology of urolithiasis is constantly evolving, analyzing the composition of stones is crucial to better understand the determinants of lithogenesis. The aim of this study was to describe the composition of stones of pediatric patients in a tertiary center. Clinical and metabolic data from all pediatric patients with at least one stone that was analyzed by Fourier transformed infrared spectroscopy (FTIR) in the Hospices Civils de Lyon between 2013 and 2017 were retrospectively collected. A total of 111 patients (sex ratio 1.4:1) were included; their median ([IQR]) age was 7.5 (3.1-10.5) years. The main component of stones was calcium oxalate (weddellite for 34 (31%) stones, whewellite 23 (21%)), calcium phosphate (carbapatite 32 (29%), brushite 6 (5%), amorphous calcium phosphate 3 (3%)), struvite 5 (5%), cystine 4 (4%), uric acid 2 (2%), and ammonium acid urate 2 (2%). A total of 20 (18%) stones were pure and 24 (22%) were infectious. Carbapatite stones were the most frequent in patients < 2 years and calcium oxalate stones in patients > 2 years old. Metabolic abnormalities (most frequently hypercalciuria) were found in 50% of tested patients and in 54% of patients with infectious stones. Congenital anomalies of the kidney and/or urinary tract (CAKUT) or neurogenic bladder were present in 9/24 (38%) patients with infectious stones and 12/16 (76%) patients with bladder stones.Conclusion: This study confirms that calcium oxalate stones are the most frequent among pediatric patients, which could reflect the nutritional habits of predisposed patients. In contrast, infectious stones are less frequent and occur mostly in association with anatomic or metabolic favoring factors.

Disseminated bartonellosis in a child with steroid-dependent nephrotic syndrome receiving mycophenolate mofetil monotherapy.

Cat scratch disease, usually a benign infectious disease, may develop as multisystem disease with multiorgan involvement, particularly in immunocompromised patients. We report on a patient who developed disseminated bartonellosis while receiving mycophenolate mofetil monotherapy treating steroid-dependent nephrotic syndrome, highlighting that severe infection can be observed in those patients. Therefore, this category of patients should be cautious when having contact with kittens and receives proper prevention advice.

Tyrosinemia type 1 in pediatric nephrology: Not always straightforward.

The main clinical features of tyrosinemia type 1 usually appear in the first months of life, including fever, diarrhea, vomiting, liver involvement, growth failure, and renal proximal tubulopathy with subsequent hypophosphatemic rickets. An early diagnosis is crucial in order to provide specific management and to prevent complications. Here, we report on two cases referred primarily to pediatric nephrologists for the diagnosis of "neonatal tubulopathy" and management of "X-linked hypophosphatemia (XLH)," respectively. Our aim is to emphasize that (1) even a mixed tubulopathy can reveal tyrosinemia, and (2) tyrosinemia is a classic differential diagnosis of XLH that should not be forgotten, especially in the era of the anti-FGF23 burosumab.

[Interferent RNA treatment: Example of primary hyperoxaluria]. / Traitement par ARN interférent : exemple de l'hyperoxalurie primitive.

Primary hyperoxalurias are rare disease with autosomal recessive inheritance; they often lead to kidney failure and can lead to life-threatening conditions, especially in early onset forms. There are three types, responding to distinct enzyme deficits. Type 1 represents 85% of cases and results from an enzyme deficiency (alanine-glyoxylate aminotransferase) in the peroxisomes of the liver, causing hyperoxaluria leading to urolithiasis with or without nephrocalcinosis. As glomerular filtration decreases, a systemic overload appears and spares no organ. Treatment has hitherto been based on combined liver and kidney transplantation, with significant mortality and morbidity. The recent introduction of interfering RNA treatments opens up new perspectives. By blocking an enzymatic synthesis (glycolate oxidase or lacticodehydrogenase a) upstream of the deficit that causes the disease, oxaluria normalizes and the tolerance of the drug (administered by injection every 1 to 3 months) is good. This strategy will help prevent kidney failure in patients treated early and avoid liver transplantation in those who are diagnosed at an advanced stage of kidney failure.