Long-term clinical outcomes with an average of 6 years follow-up in dRTA patients treated with ADV7103 an oral twice-daily fixed and prolonged-release combination of potassium bicarbonate and potassium citrate (Sibnayal®).

Long-term clinical outcomes with an average of 6 years follow-up in dRTA patients treated with ADV7103 an oral twice-daily fixed and prolonged-release combination of potassium bicarbonate and potassium citrate (Sibnayal®). | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Long-term clinical outcomes with an average of 6 years follow-up in dRTA patients treated with ADV7103 an oral twice-daily fixed and prolonged-release combination of potassium bicarbonate and potassium citrate (Sibnayal®). Aurelia Bertholet-Thomas, Aurelie de-mul, Gwenaëlle Roussey-Kesler, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4957828/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Aug, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Distal renal tubular acidosis (dRTA) is a rare disease characterized by hyperchloremic metabolic acidosis affecting growth, bone and kidney health. Methods: The aim of B22CS study was to evaluate long-term safety and efficacy of ADV7103, a prolonged-release alkalizing formulation with twice daily dosing, in children and adults with dRTA. Results: A total of 30 patients with inherited dRTA (mean age:10.6±6.0 years) already treated with ADV7103 entered this long-term study (average of 6 years). ADV7103 was well tolerated over the study duration. ADV7103 allowed a sustained control of metabolic acidosis as plasma bicarbonate level was 22.0±3.2 mmol/L at baseline versus 22.6±2.5 mmol/L at the End of Follow-up (EoF), p=NS. From baseline to EoF, mean Z-score height significantly increased (-0.6±1.0 to -0.3±1.0, p=0.03), without significant change in weight and body mass index. Kidney function remained stable from baseline to EoF: estimated glomerular filtration rate =105±17 and 104±20 mL/min/1.73m2, respectively, p=NS. Urinary ratios: Calcium/Creatinine (UCa/UCr), Citrate/Creatinine (UCi/UCr), Calcium/Citrate (UCa/UCi) were not significantly different between baseline and EoF (p=NS). Both percentages of patients with nephrocalcinosis and with nephrolithiasis remained stable between baseline and EoF (p=NS). Mean lumbar bone mineral density Z-score significantly increased from baseline (-1.1±1.0) to EoF (-0.8±1.0), p=0.005, with significant improvement between baseline and EoF in pre- and post-pubertal patients (p=0.035 and p<0.001, respectively), whilst it was maintained in pubertal patients (p=NS). Conclusion. Long-term data support the good safety and efficacy profile of ADV7103 in the treatment of dRTA with adequate control of metabolic acidosis, stable kidney function and significant positive long-term clinical outcomes. Bone metabolism Bone Mineral Density distal Renal Tubular Acidosis estimated Glomerular Filtration Rate growth Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Key learning points What was known (maximum 50 words) : The medical management of dRTA consists in the correction of metabolic acidosis to prevent long-term complications on growth, bone metabolism and kidney function. Growth and kidney function were shown to be correlated to metabolic control. Only half of patients had adequate metabolic control. More than 80% of adult patients had CDK KDIGO≥2. This study adds (maximum 50 words) : For the first time, a long-term follow-up study provides safety and efficacy data of Sibnayal®, an alkali medication with long-lasting release allowing 2 intakes per day. This study supports a long-term adequate control of metabolic acidosis with Sibnayal®, along with significant clinical outcomes on growth, kidney function and bone metabolism. Potential impact (on practice or understanding, maximum 50 words) : The main challenge for physicians is to prevent long-term complications of dRTA by better controlling metabolic acidosis. Sibnayal® as an innovative prolonged-release alkalizing formulation with twice daily dosing, adapted for children, contributes to improving current medical management, clinical outcomes and quality of life of dRTA patients. Background Distal renal tubular acidosis (dRTA) is a rare tubular disease that can be inherited (with sensorineural hearing impairment in some genetic forms) and may also be acquired especially in adults 1 . The disorder is characterized by hyperchloremic metabolic acidosis with normal plasma anion gap, usually associated with hypokalemia. It induces negative effects on bone health and growth, such as stunting and failure to thrive, rickets in children, and osteomalacia in adults, which can be corrected with adequate control of metabolic acidosis 2–5 . Hypercalciuria and hypocitraturia observed in dRTA lead to nephrocalcinosis, nephrolithiasis and chronic kidney disease (CKD) 2–5 . Concerning inherited dRTA, recent European guidelines from the European Rare Kidney Disease Reference Network (ERKNet) and the European Society of Paediatric Nephrology (ESPN) have delineated the management of such patients 1 . Alkalizing therapy aims at normalizing bicarbonate levels to control metabolic acidosis and at preventing long-term complications 5 . The current Standard of Care (SoC) consists of alkalizing products, administered 3 to 6 times per day. The low gastrointestinal tolerability and bad taste of most alkali treatments, leading to poor adherence, explain that only half of patients have an adequate control of metabolic acidosis 5 . As an alternative, ADV7103, a prolonged-release granules and tasteless formulation of potassium citrate and potassium bicarbonate, allows a 12 hour-effect after a single dose, and is well tolerated 6 . In adult and pediatric patients with dRTA, ADV7103 has demonstrated an improved control of plasma bicarbonate levels, a surrogate marker of metabolic acidosis, over SoC treatments currently available, together with good acceptability and tolerability 7 . After 24 months of treatment with ADV7103, the safety, tolerability, efficacy, and compliance to treatment in these patients were maintained 8 . The aims of the B22CS study were to evaluate the long-term safety and efficacy of ADV7103, in pediatric and adults dRTA patients, with an average follow-up of 6 years. Materials and Methods Study design As previously reported, all study patients had inherited dRTA 8 . Patients were divided into 4 age-groups: adults ≥ 18 years old, teenagers [12–18 years old [, children [4–12 years old [, and infants/toddlers [6 months-4 years old [. They were previously enrolled in a multicenter phase II/III trial, B21CS (EudraCT 2013-002988-25) having demonstrated the non-inferiority and then the superiority of ADV7103 as compared to SoC to maintain plasma bicarbonate level in the normal range 7 . These patients were then invited to participate in the multicenter, single-arm, open-label, follow-up B22CS study (EudraCT 2013-003828-36). At baseline visit (last visit of phase II/III trial), all patients were already treated by ADV7103. The study was first analyzed after a short follow-up period of 24 months 8 , and we present here the results of the long-term 6-year follow-up period with yearly visits (Fig. 1 ). All patients were included in the efficacy and safety analyses. Patients received doses of ADV7103 twice daily, adjusted to reach normal plasma bicarbonate levels, as defined in each local laboratory and assessed by each clinical Investigator. Safety evaluation Treatment emergent adverse events (TEAEs) were recorded with their severity and relationship to the treatment. The number and percentage of patients presenting TEAEs by system organ class and preferred term, according to the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0), were calculated. Anthropometric and pubertal evaluations Height (cm), weight (kg), and Body mass index (BMI) (kg/m 2 ) were measured at yearly visits and expressed as Z-scores for age according to World Health Organization standards 9,10 . Height, weight and BMI Z-scores <-2.0 were considered for failure to thrive and stunting 11,12 . Genetic target height was determined from parents’ final height, according to the American College of Medical Genetics practice guideline 13 . The Estimated Adult Stature (EAS) was calculated at baseline, Month 24, Month 48 and EoS as the height at Tanner stage 5 or the extrapolated height at 19 years (considering the Z-score at the time of evaluation). The EAS was considered normal when it was within the range target height ± 10 cm for boys and target height ± 9 cm for girls 14 . Pubertal maturity was evaluated according to Tanner stage standard tables containing the age percentiles for each stage in the reference population 15–17 . Assessments of tubular damages and kidney function The following parameters were measured in local laboratories: plasma bicarbonate, kalemia and creatininemia, urinary pH (evaluated by glass electrode pH-meter), ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR), urine calcium/creatinine ratio (UCa/UCr), urine citrate/creatinine ratio (UCi/UCr), and urine calcium/citrate ratio (UCa/UCi). Normal ranges were provided from published data depending on patient age and gender 18–21 . The estimated glomerular filtration rate (eGFR) was calculated according to the CKiD Under 25 (CKiDU-25) Eq. 2 2 . Decreased kidney function was considered when eGFR was < 90 mL/min/1.73 m 2 , with CKD stages according to Kidney Disease Improving Global Outcomes guidelines 23 . The risk of lithogenesis was evaluated with a threshold of UCa/UCi above 3.0 mmol/mmol and UCa/UCr above normal range according to age 24 . Crystalluria analyses were performed in local laboratories with focus on amorphous carbonated calcium phosphate (ACCP) crystals that are specific to dRTA. Crystalluria was evaluated by the examination of a well-homogenized fresh morning urine sample set in a Malassez cell by light microscopy. The presence or absence of nephrocalcinosis (without grading) and nephrolithiasis was assessed at each visit mainly by kidney ultrasounds and possibly computed tomography (CT)-scan when it was available for adult patients. Bone biomarkers assessment Rickets and osteomalacia were determined following investigator’s clinical judgement, based on clinical signs (diffuse bone and joint pain, myalgia, muscle weakness, abnormal posture, abnormal stature, walking difficulty), radiologic signs (abnormal bone aspect, bone deformation, pseudofracture) and biochemical signs (abnormal values of plasma bone alkaline phosphatases (bALPs), calcium and phosphate). Bone and phosphate/calcium metabolism biomarkers were assessed up to Month 48 in a central laboratory for 1-25-dihydroxy-vitamin D (1-25-OH-vit-D, normal range: 69–200 pmol/L), bALPs, (normal values depending on age and gender), parathyroid hormone (PTH, normal range: 5.5–38.4 ng/L). In contrast, 25-hydroxy-vitamin D (25-OH-vit-D), plasma phosphate and calcium were performed in local laboratories. Plasma phosphate and bALPs were expressed as Z-scores for age and gender 25,26 . Bone Mineral Density (BMD, g/cm 2 ) was measured yearly in three skeletal regions (lumbar spine, hip and whole body) using dual-energy X-ray absorptiometry (DXA) and expressed as Z-score. Only lumbar spine area results are presented as this is the only relevant skeletal area for both pediatric and adult populations. Values of Z-score <-2.0 SD were considered below the normal range according to the recommendations of the International Society for Clinical Densitometry 27 . Evaluation of compliance to treatment Patients were asked to return their unused treatment units (sachets) to calculate the proportion of treatment that had been taken versus what should have been taken according to study protocol. When patients did not return unused sachets, compliance was estimated by questioning the patient and/or his/her family while considering laboratory results. In case of doubt, treatment was considered as not taken by the patient. Treatment compliance was qualified “poor” when compliance rate was < 50%, “average” at 50 to 90%. Statistical analyses The final data analysis included data collected from November 2014 to the end of the study dated October 2021. All patients receiving at least one dose of ADV7103 and with at least one efficacy assessment were included in the efficacy analysis set. Safety and efficacy data and their change from baseline (when appropriate) were summarized over time using descriptive statistics by age group (according to age at baseline) or considering pooled pediatric patients and the overall patient population. The originally planned statistical analyses B22CS studies were mainly descriptive from baseline to End of Study (EoS, last visit in the study), except for a repeated measures model on change from baseline adjusted on baseline for lumbar spine BMD Z-scores. All other statistical tests and associated figures were performed as post-hoc analyses. For these post-hoc analyses, an End of Follow-up (EoF) value corresponding to the last available patient value for each parameter was computed. The EoF values were compared to baseline values, to assess the evolution of parameters between first and last measurements. The value measured during the EoS visit was used when assessing the evolution of a parameter over time throughout the study. Data were described as proportions or mean (± standard deviation, ±SD) according to the nature of the parameter. To compare two quantitative values (mean at baseline versus EoF for instance), a paired Student’s t-test or a Wilcoxon signed-rank test was used depending on if the data is normally distributed or not, respectively (normality was assessed using Skewness and Kurtosis values as well as graphical checks). When proportions were compared (number of patients in normal range at baseline versus EoF for instance), a McNemar’s test (when two categories are involved) or a symmetry test (when more than two categories are involved) was used. To evaluate the evolution of a parameter over time, a repeated measures model on change from baseline, adjusted on baseline, was performed. Values of mean least squares and 95% confidence interval (CI) were reported for the difference between each visit and baseline. All statistical tests were two-sided and carried out at the 5% level of significance. These tests were performed for exploratory purposes only and no adjustment for multiplicity was performed. Most tests are displayed with a graphical representation. Analyses were performed using SAS® software, Version 9.4 (SAS Institute Inc., Cary, NC, USA). Results Main data of B22CS patients are summarized in Table 1. Patients’ characteristics A total of 30 patients (6 adults, 8 teenagers, 13 children and 3 infants), all presenting with inherited dRTA, entered the long-term study, 27 of whom had data collected beyond Month 30 ( Figure 1 ). The mean age (years) of patients were 10.6±6.0 (min-max: 2-21) at baseline and 16.4±6.0 (min-max: 7.8-28.0) at EoF, respectively. Mean and median durations (years) of follow-up were 5.8±1.3 and 6.3 (min-max:1.1-6.8), respectively ( Table 1 ). A total of 22 patients (73%) underwent genetic analysis, that found pathogenic variants in 21 patients (ATP6V0A4, N=9, ATP6V1B1 N=12) while the genetic mutation was not identified for 1 patient. Hearing impairment was reported in 20 patients, including all 6 adults. Safety Over the course of the study, a total of 309 TEAEs were experienced by 29 patients. The most frequently reported TEAEs were vitamin D deficiency (13 patients, 43.3%), hypokalemia (8 patients, 26.7%), iron deficiency (7 patients, 23.3%) and decreased appetite (2 patients, 6.7%). Of all TEAEs, 13 (4%) TEAEs were related to treatment, reported in 6 patients (20%). The majority of these related TEAEs were gastrointestinal disorders (N=11), reported in 5 patients (16.7%), and were of mild or moderate intensity, resolving without discontinuation of the treatment. No serious adverse events related to the treatment were reported ( Supplemental Table S1 ). Changes in pubertal maturity and growth Pubertal maturity was normal in most pediatric patients throughout the study (>90%). Overall, 11/23 pediatric patients (48%) (including 7/8 teenagers [87%]) reached Tanner Stage 5 by EoS. Mean height Z-score significantly increased between baseline and EoF (-0.6±1.0 to ‑0.3±1.0, p=0.03) ( Figure 2A ) (descriptive analysis by age group and in all patients in Supplemental Figure S1 ), whilst mean weight and BMI Z-scores remained stable (p=NS) ( Figures 2B, 2C ) ( Table 1 ). In addition, the increase in mean height Z-score overtime was significantly greater in patients with abnormal EAS at baseline (N=6) as compared to patients with normal EAS at baseline (N=20) (p<0.001) ( Figure 3 ). Overall, most patients had a normal EAS at baseline. The proportion of patients with a normal EAS remained stable throughout the study from 20/26 patients (77%) at baseline to 21/26 patients (81%) at EoF, (p=NS) ( Table 1 ). Among the 6 patients with abnormal EAS at baseline, 4 patients reached a normal EAS at EoF. Evolution of tubular damages and kidney function Mean plasma bicarbonate levels remained stable throughout the 6-year follow-up from 22.0±3.2 at baseline to 22.6±2.5 mmol/L at EoF, p=NS ( Figure 4 ). When only considering patients with blood samples taken before study treatment intake, the same evolution profile was shown. Mean plasma potassium levels were also stable over the study duration, from 3.8±0.5 at baseline to 3.7±.0.4 mmol/L at EoF, p=NS ( Figure 5 ). Mean eGFR values remained stable over time, from 105±17 at baseline to 104±20 mL/min/1.73 m 2 at EoF, p=NS ( Table 1 ). Among 23 patients with an eGFR measurement, 20 patients had CKD stage 1 at baseline (87%) and 17 patients (74%) at EoF. In addition, 3 patients had CKD stage 2 at baseline (13%) and 6 patients at EoF (26%). There was no statistical difference in CKD stages breakdown between baseline and EoF (p=NS) and no patient reached CKD stage 3 to 5 during the study ( Table 1 ). Urinary ratios associated with the risk of nephrolithiasis/nephrocalcinosis (UCa/UCr, UCi/UCr and UCa/UCi) were not significantly different between baseline and EoF (p=NS) ( Table 1 ). The percentage of patients with positive crystalluria tended to decrease (53% at baseline and 35% at EoF, p=NS). There was no significant increase in the occurrence of ACCP crystals, 47% patients at baseline versus 35% patients at EoF, p=NS. ( Table 1 ). The proportion of patients with urinary pH in the 7-8 range was stable across the study (70% at baseline and EoF). The proportion of patients with urine pH 8 respectively varied from 9% and 22% at baseline to 0% and 30% at EoF, p=NS. So, there was no impact on ACCP crystals presence despite some patients with urinary pH >8 ( Table 1 ). Kidney ultrasounds / CT scans The number of patients presenting nephrolithiasis increased from 6/28 patients (21%) at baseline to 11/28 patients (39%) at EoF, p=NS. Only one case of surgical procedure for kidney stone removal during the study course was reported. Nephrocalcinosis was present in 25/28 of patients (89%) at baseline and in 26/28 patients (93%) at EoF, p=NS. Nephrocalcinosis appeared in 3 patients during the study and 2 patients with nephrocalcinosis at baseline had no more nephrocalcinosis detected by imaging at EoF. Evolution of bone biomarkers None of the adults were diagnosed with osteomalacia throughout the study. Rickets was reported in 1 infant at baseline and 4 pediatric patients at Month 36 (2 children and 2 teenagers). From Month 60, rickets were no longer reported in patients. PTH levels remained in the normal range over 48 months: 15.6 ± 8.2 to 16.6 ± 6.6 ng/L at baseline and Month 48, respectively, p=NS ( Table 1 ). Concerning bALP levels, most patients (from 75% to 96%, according to the study visit) had levels in the normal range over 48 months and mean bALP Z-score was maintained from baseline to Month 48 in the overall population, p=NS. Mean serum phosphate Z-score significantly decreased over 48 months from -0.7±0.7 to -1.4±1.1, p=0.005 ( Supplemental Figure S2 ). Mean TmP/GFR also significantly decreased from 1.5±0.2 at baseline to 1.3±0.3 mmol/L at EoF, p=0.001. Mean circulating calcium levels slightly increased from 2.38±0.10 at baseline to 2.42±0.08 mmol/L at EoF, p=0.048. Mean serum 25-OH-vit-D levels were low during the study (55.0±33.7 at baseline and 51.0±19.2 nmol/L at Month 48) while mean serum 1-25-OH-vit-D levels were in the normal ranges (164.6±54.1 at baseline and 158.6±36.3 pmol/L at Month 48), p=NS ( Table 1 ). Evolution of bone mineral density A significant improvement in mean lumbar spine BMD Z-score was observed from baseline (-1.1±1.0) to EoF (-0.8±1.0), p=0.005. Lumbar spine BMD Z-scores were normal in most patients from baseline (71%) to EoF (87%) ( Table 1 ). Over the study duration, lumbar spine BMD Z-score evolution was not statistically significant, while the change from baseline to each yearly visit was statistically significant using the same statistical test ( Figure 6 ). Mean lumbar spine BMD Z-score varied according to patients’ pubertal status with a significant improvement from baseline to EoF in pre-and post-pubertal patients while it was maintained in patients in pubertal phase: -1.2±1.3 at baseline and -0.5±0.9 at EoF, p=0.035 in pre-pubertal patients, -1.0±1.0 at baseline and -0.4±0.8 at EoF, p<0.001 in post-pubertal patients and -1.2±0.9 at baseline and -1.3±1.0 at EoF, p=NS in pubertal patients ( Figure 7 ). ADV7103 dose and compliance The overall mean dose prescribed evolved from 3.4±1.7 at baseline to 2.3±1.1 mEq/kg/d at EoS ( Supplemental Figure S3 ). The compliance rate was good or excellent in 58% to 83% patients, depending on the time considered. At EoS, compliance rate was good to excellent for 16/27 patients (60%). Compliance was lower in teenagers whose compliance rate was poor at EoS for 4/7 teenagers (57%) compared to 0/5 adults, 1/12 children (8%) and 0/3 infants ( Supplemental Figure S4 ). Discussion In dRTA patients, metabolic acidosis control is the main goal to prevent short and long-term complications of the disease 28–31 . This objective can be highly challenging to attain for patients carrying H + -ATPase variants 32,33 , as it is the case in 85% of the present population. Thus, the current challenge for pediatric and adult nephrologists in dRTA is to improve the proportion of patients displaying adequate metabolic control and to have robust outcome data to prevent long-term complications, especially on growth, bone metabolism and kidney function. Few long-term outcome data have been reported to date. A collaborative work between ERKNet and the European Renal Association collecting data from a large European multinational cohort of dRTA patients is ongoing 34 . Lopez-Garcia et al. reported data from a large cohort of 340 patients (29 countries) with a median age at last follow-up of 11.0 (0.0–70.0) years 5 . The median prescribed dose of alkali treatment was 1.9 mEq/kg/d. Only 51% of patients achieved adequate metabolic control under alkali treatment, keeping in mind that higher bicarbonate plasma levels were associated with better growth and kidney function. ADV7103 is a prolonged-release formulation of potassium citrate and potassium bicarbonate with a twice daily administration, approved by the European Medical Agency in April 2021 in the treatment of patients with inherited or acquired dRTA, aged one year and older. ADV7103 has been developed over the last decade from a collaboration between French physicians and a pharmaceutical company in response to a direct request from clinicians. A superiority to maintain plasma bicarbonate levels compared to SoC was demonstrated in a short-term study 7 . In addition, over 24 months, a sustained control of metabolic acidosis was shown together with a good treatment acceptability and an improvement of Quality of Life (QoL) (quantitative assessment) 8 . In addition, a long-term QoL analysis (qualitative assessment) was done using semi-structured interviews with patients and/or parents after at least 48 months of treatment, with an average of 5 years. Results were previously published and showed a high level of patients/parents’ satisfaction 35 . The good safety profile over 24 months previously published was confirmed over 6 years and no additional safety or tolerability concerns associated to the use of ADV7103 were raised. No pattern of increasing adverse events (treatment-related or not) was observed with increasing duration of exposure to the treatment. The present study also confirms the long-term efficacy of ADV7103 to maintain normal plasma bicarbonate levels. A total of 73% of patients indeed displayed normal plasma bicarbonate after an average 6-year follow-up. As shown in Lopez-Garcia’s cohort 5 , adequate metabolic control is significantly linked with growth improvement. With ADV7103, mean height Z-score significantly increased without BMI increase. The improvement of height in the adult group may be explained by the mean age of this group at inclusion (19.0 ± 0.1 years). The most significant growth improvement was observed in patients with abnormal EAS at baseline. Our data confirmed that an adequate metabolic acidosis control allowed a better growth prognosis for patients including young adult patients. Kidney function in patients with dRTA declines significantly earlier than in general population, CKD affecting indeed at least a third of dRTA patients from the second decade of life 3–5,32 . When considering the comparable age patient subset from Lopez-Garcia’s cohort 5 , (n = 167, mean age: 15.0 ± 5.0 years): 45.5% of their patients were CKD stage ≥ 2 versus 26.0% in our study. We observe a noticeable improvement of eGFR in our study. For the first time, we report a promising stabilization of kidney function during the long-term observation period in dRTA patients receiving ADV7103. In our study, and as already reported in retrospective studies 3–5,32,36 , nephrocalcinosis was reported in most patients at baseline, leading to difficult interpretation of ADV7103 effect on this parameter. Over the study duration, calciuria and citraturia were maintained in normal range, in 90% and 45% of patients, respectively (stable risk of lithogenesis). So, we could expect a decrease in intra-tubular crystallization and of calcium deposits in the kidney which could protect renal function 37,38 . Nephrolithiasis was stable among patients between baseline and EoF. There was only one case of kidney stone removal during the 6-year study, while this event has been reported as the most frequent during the dRTA patient management 39 . An additional major concern for physicians is the bone and mineral management of dRTA patients as there is few published data about the correction of bone parameters with alkali treatments. In a small cohort of adult patients with secondary dRTA (N = 14), Domrongkitchaiporn et al. reported osteopenia, fractures and significantly low BMD 40,41 . After one year of alkali therapy, they showed a significant increase in BMD and a normalization of bone formation rate. They hypothesized that chronic metabolic acidosis results in a suppression of bone formation and resorption, as previously shown in experimental papers demonstrating a deleterious effect of acidosis both on osteoblastic differentiation and osteoclastic differentiation/activity 42–44 . In our study, most bone markers remained in the normal range, specifically bALPs, while a significant decrease in mean serum phosphate Z-score and TmP/GFR was observed. This suggests an increase in bone mass, improvement of bone modeling rate and mineralization. This is supported by a continuous and significant improvement of lumbar spine BMD Z-score, expressed as change from baseline. It can nevertheless also be argued that serum phosphate levels decrease with age, and particularly during childhood and adolescence, but the data were analyzed using standardization for age to avoid this age-specific effect. These positive long-term effects of ADV7103 are linked to its efficacy but also likely to the good compliance to treatment maintained throughout the follow-up except in teenagers where high prevalence of poor adherence to chronic treatments is well-known 45 . This age group is known to require specific multidisciplinary teams, including social workers, psychologists, specific transition programs 46 . The main limitation of our study was the absence of a direct comparator during follow-up. However, a long-term randomized controlled trial was not considered feasible (nor ethical) in a rare disease such as dRTA. The set-up of the European dRTA registry will further consolidate the long-term evolution of dRTA patients based on alkali treatments 34 . Another limitation is the absence of morpho-constitutional analysis of stones and not enough CT imaging performed to detect and follow nephrocalcinosis and nephrolithiasis. In conclusion, treatment with ADV7103 ensures the first long-term evidence of metabolic acidosis control and prevention of long-term dRTA complications with a good safety and tolerability profile. ADV7103 significantly improves growth and lumbar spine BMD in pediatric and young adult dRTA patients. Most importantly, kidney function is preserved for a significant long period (6 years on average). Overall, these results contribute to improving the management and outcomes of this orphan disease. Declarations Ethics approval The study was approved by regional independent ethics committees (CPP sud-est II; clinical center of niš, ethics committee, Niš; Etická komisia Detská fakultná nemocnica s poliklinikou Bratislava, Bratislava) and national regulatory health authorities and conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. Consent to participate Written informed consent was obtained from all adult patients, and from the parents or legal guardians of all children. When possible, the assent from pediatric patients themselves was also obtained. Data availability statement: The data that support the findings of this study are available from ADVICENNE, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of ADVICENNE. Competing interest’s statement: A. Bertholet-Thomas received travel and speaker fees from Advicenne. J. Bacchetta received speaker fees from Advicenne. L. Chidler and V. Leblanc are Advicenne’s employees. Funding: This study was funded by Advicenne. Authors‘ contributions: Aurelia Bertholet-Thomas: Global concept of the clinical trial, patient enrollment and management, data collection and interpretation, manuscript writing and critical review of the manuscript. Justine Bacchetta: Patient enrollment and management, data collection and interpretation and critical review of the manuscript. Julie Bernardor: Data interpretation and critical review of data. Aurélie De Mul: Data interpretation and critical review of data. Gwenaëlle Roussey-Kesler, Ludmila Podracka, Robert Novo, François Nobili, Bertrand Knebelmann, Jérôme Harambat, Emilija Golubovic, Olivia Boyer, Massimo Di Maio, Mathilde Cailliez, and Véronique Baudouin: Patient enrollment and management, data collection and critical review of the manuscript. Laure Chidler, Véronique Leblanc: Critical review of data, manuscript writing. Consent for publication : All authors consent for publication. Acknowledgements: The authors acknowledge the Investigators of B22CS study and their corresponding Clinical Investigation Centers for their involvement in conducting the clinical trial. We thank Camilo Lopez Garcia, MD and Detlef Böckenhauer, MD, PhD for the agreement of use of their data in the discussion of this article. The authors thank Advicenne for the initiation of this clinical program. This work benefited from the collaboration of members of French Orphan Kidney Disease Network (ORKiD), of the European Rare Kidney Disease Reference Network (ERKNet) and of the European Reference Network for Rare Bone Diseases (ERN BOND). TRIAL REGISTRATION NUMBER Registered as EudraCT 2013-003828-36 on September 03, 2013. References Trepiccione F, Walsh SB, Ariceta G, et al. Distal renal tubular acidosis: ERKNet/ESPN clinical practice points. Nephrol Dial Transplant . 2021;36(9):1585-1596. doi:10.1093/ndt/gfab171. Vallés PG, Batlle D. Hypokalemic Distal Renal Tubular Acidosis. Adv Chronic Kidney Dis . 2018;25(4):303-320. doi:10.1053/j.ackd.2018.05.003. Gómez-Conde S, García-Castaño A, Aguirre M, et al. Molecular aspects and long-term outcome of patients with primary distal renal tubular acidosis. Pediatr Nephrol . 2021;36(10):3133-3142. doi:10.1007/s00467-021-05066-z. Forero-Delgadillo JM, Gil-Peña H, Alonso-Varela M, Santos F; RenalTube Group. Kidney function in patients with primary distal renal tubular acidosis. Pediatr Nephrol . 2021;36(7):1931-1935. doi:10.1007/s00467-021-05068-x. Lopez-Garcia SC, Emma F, Walsh SB, et al. Treatment and long-term outcome in primary distal renal tubular acidosis. Nephrol Dial Transplant . 2019;34(6):981-991. doi:10.1093/ndt/gfy409. Guittet C, Roussel-Maupetit C, Manso-Silván MA, Guillaumin F, Vandenhende F, Granier LA. Innovative prolonged-release oral alkalising formulation allowing sustained urine pH increase with twice daily administration: randomized trial in healthy adults. Sci Rep . 2020;10(1):13960. Published 2020 Aug 18. doi:10.1038/s41598-020-70549-2. Bertholet-Thomas A, Guittet C, Manso-Silván MA, et al. Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments. Pediatr Nephrol . 2021;36(1):83-91. doi:10.1007/s00467-020-04693-2. Bertholet-Thomas A, Guittet C, Manso-Silván MA, et al. Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis. Pediatr Nephrol . 2021;36(7):1765-1774. doi:10.1007/s00467-020-04873-0. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl . 2006;450:76-85. doi:10.1111/j.1651-2227.2006.tb02378.x. de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ . 2007;85(9):660-667. doi:10.2471/blt.07.043497. WHO Multicentre Growth Reference Study Group. Assessment of differences in linear growth among populations in the WHO Multicentre Growth Reference Study. Acta Paediatr Suppl . 2006;450:56-65. doi:10.1111/j.1651-2227.2006.tb02376.x. Wang Y, Chen H-J. Use of percentiles and Z-scores in anthropometry. In: Preedy VR, ed. Handbook of anthopometry: Physical measures of human form in health and disease . Springer. 2012: 29-48. doi:10.1007/978-1-4419-1788-1_2. Seaver LH, Irons M; American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee. ACMG practice guideline: genetic evaluation of short stature. Genet Med . 2009;11(6):465-470. doi:10.1097/GIM.0b013e3181a7e8f8. Zhang Z, Shoff SM, Lai HJ. Incorporating genetic potential when evaluating stature in children with cystic fibrosis. J Cyst Fibros . 2010;9(2):135-142. doi:10.1016/j.jcf.2010.01.003. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child . 1969;44(235):291-303. doi:10.1136/adc.44.235.291. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child . 1970;45(239):13-23. doi:10.1136/adc.45.239.13. WHO Sexual and Reproductive Health and Research. The sexual and reproductive health of younger adolescents in developing countries: research issues in developing countries. 2011. Matos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr . 1997;131(2):252-257. doi:10.1016/s0022-3476(97)70162-8. Frey J, Daudon M, Raby N, et al. Valeur séméiologique des paramètres biochimiques urinaires [Clinical value of urinary biochemical parameters]. Ann Biol Clin (Paris) . 2001;59(1):13-25. Kirejczyk JK, Porowski T, Konstantynowicz J, et al. Urinary citrate excretion in healthy children depends on age and gender. Pediatr Nephrol . 2014;29(9):1575-1582. doi:10.1007/s00467-014-2806- Derain Dubourg L, Aurelle M, Chardon L, Flammier S, Lemoine S, Bacchetta J. Tubular phosphate handling: references from child to adulthood in the era of standardized serum creatinine. Nephrol Dial Transplant . 2022;37(11):2150-2156. doi:10.1093/ndt/gfab331. Pierce CB, Muñoz A, Ng DK, Warady BA, Furth SL, Schwartz GJ. Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int . 2021;99(4):948-956. doi:10.1016/j.kint.2020.10.047. Group Kidney Disease: Improving Global Outcomes (KDIGO). Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. Supplements. 2013;3(1):1-150. Parent X, Boess G, Brignon P. Lithiase oxalocalcique. Relation entre facteurs de risque biochimiques et phase cristalline du calcul. Prog Urol. 1999;9:1051-1056. Ardeshirpour L, Cole DE, Carpenter TO. Evaluation of bone and mineral disorders. Pediatr Endocrinol Rev . 2007;5 Suppl 1:584-598. Cavalier E, Rozet E, Carlisi A, et al. Analytical validation of serum bone alkaline phosphatase (BAP OSTASE) on Liaison. Clin Chem Lab Med . 2010;48(1):67-72. doi:10.1515/CCLM.2010.019. Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. J Clin Densitom . 2013;16(4):455-466. doi:10.1016/j.jocd.2013.08.004. Green J, Maor G. Effect of metabolic acidosis on the growth hormone/IGF-I endocrine axis in skeletal growth centers. Kidney Int . 2000;57(6):2258-2267. doi:10.1046/j.1523-1755.2000.00086.x. Arnett TR. Acidosis, hypoxia and bone. Arch Biochem Biophys . 2010;503(1):103-109. doi:10.1016/j.abb.2010.07.021. Brown DD, Roem J, Ng DK, et al. Low Serum Bicarbonate and CKD Progression in Children. Clin J Am Soc Nephrol . 2020;15(6):755-765. doi:10.2215/CJN.07060619. Bajpai A, Bagga A, Hari P, Bardia A, Mantan M. Long-term outcome in children with primary distal renal tubular acidosis. Indian Pediatr . 2005;42(4):321-328. Palazzo V, Provenzano A, Becherucci F, et al. The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis. Kidney Int . 2017;91(5):1243-1255. doi:10.1016/j.kint.2016.12.017. Giglio S, Montini G, Trepiccione F, Gambaro G, Emma F. Distal renal tubular acidosis: a systematic approach from diagnosis to treatment. J Nephrol . 2021;34(6):2073-2083. doi:10.1007/s40620-021-01032-y. Giaccari M, Haffner D, Schaefer F et al. First interim analysis of the international distal renal tubular acidosis registry Nephrol Dial Transplant. 2023;38 Vol. 38; pp. I4 - I4.Oxford University Press (OUP) (Abstract 4989). Acquadro M, Marrel A, Manso-Silván MA, Guittet C, Joukoff S, Bertholet-Thomas A. Lived experiences of patients with distal renal tubular acidosis treated with ADV7103 and of their caregivers: a qualitative study. Orphanet J Rare Dis . 2022;17(1):141. Published 2022 Mar 28. doi:10.1186/s13023-022-02294-w. Alonso-Varela M, Gil-Peña H, Coto E, et al. Distal renal tubular acidosis. Clinical manifestations in patients with different underlying gene mutations. Pediatr Nephrol . 2018;33(9):1523-1529. doi:10.1007/s00467-018-3965-8. Verkoelen CF, Verhulst A. Proposed mechanisms in renal tubular crystal retention. Kidney Int . 2007;72(1):13-18. doi:10.1038/sj.ki.5002272. Vervaet BA, Verhulst A, De Broe ME, D'Haese PC. The tubular epithelium in the initiation and course of intratubular nephrocalcinosis. Urol Res . 2010;38(4):249-256. doi:10.1007/s00240-010-0290-5. Mumford A, Mumford J, Donald S, et al. The Economic Impact and variability of managing Distal Renal Tubular Acidosis (dRTA) in the UK healthcare setting. (Poster PUK8) Value in Health. 2019;22. doi:10.1016/j.jval.2019.09.2692 Domrongkitchaiporn S, Pongsakul C, Stitchantrakul W, et al. Bone mineral density and histology in distal renal tubular acidosis. Kidney Int . 2001;59(3):1086-1093. doi:10.1046/j.1523-1755.2001.0590031086.x. Domrongkitchaiporn S, Pongskul C, Sirikulchayanonta V, et al. Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Kidney Int . 2002;62(6):2160-2166. doi:10.1046/j.1523-1755.2002.00656.x. Arnett T. Regulation of bone cell function by acid-base balance. Proc Nutr Soc . 2003;62(2):511-520. doi:10.1079/pns2003268. Brandao-Burch A, Utting JC, Orriss IR, Arnett TR. Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization. Calcif Tissue Int . 2005;77(3):167-174. doi:10.1007/s00223-004-0285-8. Meghji S, Morrison MS, Henderson B, Arnett TR. pH dependence of bone resorption: mouse calvarial osteoclasts are activated by acidosis. Am J Physiol Endocrinol Metab . 2001;280(1):E112-E119. doi:10.1152/ajpendo.2001.280.1.E112. Taddeo D, Egedy M, Frappier JY. Adherence to treatment in adolescents. Paediatr Child Health . 2008;13(1):19-24. doi:10.1093/pch/13.1.19. Nagra A, McGinnity PM, Davis N, Salmon AP. Implementing transition: Ready Steady Go. Arch Dis Child Educ Pract Ed . 2015;100(6):313-320. doi:10.1136/archdischild-2014-307423. Tables Table 1. Main anthropometric and biological data of Baseline, EoF, Month 48 and EoS of B22CS. Data in overall population B22CS baseline B22CS EoF p-value: comparison Baseline vs EoF Age (years) Mean±SD SEM Median Min-max N=30 10.6±6.0 1.1 9.5 2.0-21.0 N=30 16.4±6.0 1.1 15.5 7.8-28.0 NA Height Z-score Mean±SD SEM Median Min-max N=28 -0.6±1.0 0.2 -0.7 -3.3-1.5 N=28 -0.3±1.0 0.2 -0.3 -2.2-1.5 p = 0.032 Weight Z-score Mean±SD SEM Median Min-max N=29 0.2±1.5 0.3 0.0 -2.5-3.2 N=29 0.6±1.3 0.2 0.4 -1.7-3.3 p = NS BMI Z-score Mean±SD SEM Median Min-max N=28 0.3±1.5 0.3 0.3 -2.3-3.3 N=28 0.2±1.4 0.2 0.3 -2.3;2.7 p = NS EAS N patients in normal range (%) N=26 20 (77%) N=26 21 (81%) p = NS Bicarbonatemia (mmol/l) Mean±SD SEM Median Min-max N=30 22.0±3.2 0.6 22.0 13.7-29.0 N=30 22.6±2.5 0.5 22.9 17.0-27.0 p = NS Kalemia (mmol/l) Mean±SD SEM Median Min-max N=22 3.8±0.5 0.1 3.8 2.7-4.7 N=22 3.7±0.4 0.1 3.7 2.9-4.2 p = NS eGFR (mL/min/1.73 m 2 ) Mean±SD SEM Median Min-max KDIGO stage, N patients (%) Stage 1 Stage 2 Stage 3 Stage 4 N=23 105±17 3.5 100.5 79.0-149.8 20 (87%) 3 (13%) 0 (0%) 0 (0%) N=23 104±20 4.1 104.5 76.5-158.1 17 (74%) 6 (26%) 0 (0%) 0 (0%) p = NS p = NS UCa/UCr N patients in normal range, (%) N=27 27 (100%) N=27 24 (89%) p = NS UCi/UCr N patients in normal range, (%) N=20 7 (35%) N=20 9 (45%) p = NS UCa/UCi N patients in normal range (UCa/UCi <3 mmol/mmol), (%) N=20 9 (45%) N=20 6 (30%) p = NS TmP/GFR (mmol/l) Mean±SD SEM Median Min-max N=20 1.5±0.2 0.0 1.5 1.1-1.8 N=20 1.3±0.3 0.1 1.3 0.6-1.7 p = 0.001 UpH N patients (%) 8.0 N=23 2 (7.4%) 16 (69%) 5 (22%) N=23 0 (0%) 16 (69%) 7 (30%) p = NS Crystalluria N patients (%) ACCP crystal N patients (%) N=17 9 (53%) 8 (47%) N=17 6 (35%) 6 (35%) p = NS p = NS Nephrocalcinosis N patients (%) N=28 25 (89%) N=28 26 (93%) p = NS Nephrolithiasis N patients (%) N=28 6 (21%) N=28 11 (39%) p = NS Calcemia (mmol/l) Mean±SD SEM Median Min-max N=26 2.38±0.10 0.0 2.4 2.2-2.5 N=26 2.42±0.08 0.0 2.4 2.2-2.6 p = 0.048 Lumbar spine BMD ( Z-score) Mean±SD SEM Median Min-max N patients in normal range (>-2SD) (%) N=24 -1.1±1.0 0.2 -1.1 -3.2-0.6 17 (71%) N=24 -0.8±1.0 0.2 -0.8 -2.7-1.1 21 (87%) p = 0.005 p = NS Data in overall population B22CS baseline B22CS Month 48 p-value: Comparison Baseline vs Month 48 Phosphatemia (Z-score) Mean±SD SEM Median Min-max N=23 -0.7±0.7 0.1 -0.7 -2.0-1.0 N=23 -1.4±1.1 0.2 -1.2 -3.5-0.4 p = 0.005 bALPs (Z-score) Mean±SD SEM Median Min-max N=9 0.9±2.2 0.7 -0.0 -1.3-4.9 N=9 0.7±1.3 0.4 0.3 -0.6-3.0 p = NS 25-OH-vit-D (nmol/L) Mean±SD SEM Median Min-max N=9 55.0±33.7 11.2 41.0 25.0-127.3 N=9 51.0±19.2 6.4 52.0 33.0-93.0 p = NS 1-25-OH-vit-D (pmol/L) Mean±SD SEM Median Min-max N=9 164.6±54.1 18.0 172.0 100.0-230.0 N=9 158.6±36.3 12.1 159.0 111.0-200.0 p = NS PTH (ng/L) Mean±SD SEM Median Min-max N patients in normal range (%) N=15 15.6±8.2 2.13 11.7 8.2-37.2 15 (100%) N=18 16.6±6.6 1.55 16.6 7.2-37.8 18 (100%) NA Data in overall population B22CS baseline EoS Dose (mEq/kg/d) Mean±SD SEM Median Min-max N=29 3.4±1.7 0.3 3.2 1.1-8.0 N=26 2.3±1.1 0.2 2.1 1.0-5.1 1‑25‑OH‑vit‑D , 1-25‑dihydroxy‑vitamin D; 25‑OH‑vit‑D , 25‑hydroxy‑vitamin D; ACCP , amorphous carbonated calcium phosphate; bALP , blood alkaline phosphatase; BMD : bone mineral density; BMI , body mass index; EAS , estimated adult stature; eGFR , estimated glomerular filtration rate; EoF , End of Follow‑up; EoS , End of Study; KDIGO, Kidney Disease: Improving Global Outcomes; Max, maximum; Min, minimum; N, number of patients; NS, non‑significant; PTH, parathyroid hormone; SD, standard deviation; SEM, standard error of the mean; SoC, standard of care; TMP/GFR, ratio of renal tubular reabsorption of phosphorus to glomerular filtration rate; UCa/UCi, urinary ratio of calcium/citrate; UCa/UCr, urinary ratio of calcium/creatinine; UCi/UCr, urinary ratio of citrate/creatinine; UpH, urinary pH. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 13 Aug, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 07 Dec, 2024 Reviewers agreed at journal 15 Nov, 2024 Reviewers invited by journal 15 Nov, 2024 Editor assigned by journal 30 Aug, 2024 First submitted to journal 28 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4957828","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":378403574,"identity":"66db6c27-ab40-41b3-80c7-88447683e8f2","order_by":0,"name":"Aurelia Bertholet-Thomas","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Aurelia","middleName":"","lastName":"Bertholet-Thomas","suffix":""},{"id":378403575,"identity":"2ad50d0f-5e03-4d09-b00b-ed41ae3522fa","order_by":1,"name":"Aurelie de-mul","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Aurelie","middleName":"","lastName":"de-mul","suffix":""},{"id":378403576,"identity":"424bcdca-e6a1-48e2-b21e-402ac77ed679","order_by":2,"name":"Gwenaëlle Roussey-Kesler","email":"","orcid":"","institution":"CHU Nantes: Centre Hospitalier Universitaire de Nantes","correspondingAuthor":false,"prefix":"","firstName":"Gwenaëlle","middleName":"","lastName":"Roussey-Kesler","suffix":""},{"id":378403577,"identity":"0b8d7327-643b-464b-8acd-21e16bbc8593","order_by":3,"name":"Ludmila Podracka","email":"","orcid":"","institution":"Children's National: Children's National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ludmila","middleName":"","lastName":"Podracka","suffix":""},{"id":378403578,"identity":"c6b77c94-9fe4-4772-bea3-b186dc3d6403","order_by":4,"name":"Robert Novo","email":"","orcid":"","institution":"CHRU de Lille: Centre Hospitalier Universitaire de Lille","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Novo","suffix":""},{"id":378403579,"identity":"3b465b97-29a7-4559-9b0d-fca17704e1da","order_by":5,"name":"Francois Nobili","email":"","orcid":"","institution":"CHU Besancon: Centre Hospitalier Universitaire de Besancon","correspondingAuthor":false,"prefix":"","firstName":"Francois","middleName":"","lastName":"Nobili","suffix":""},{"id":378403580,"identity":"dbc5c8ec-53bd-47d7-841b-9802c89ceaa8","order_by":6,"name":"Bertrand Knebelmann","email":"","orcid":"","institution":"APHP: Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Bertrand","middleName":"","lastName":"Knebelmann","suffix":""},{"id":378403581,"identity":"431af559-5973-41cb-8b62-3c0de89205da","order_by":7,"name":"Jerome Harambat","email":"","orcid":"","institution":"CHU Bordeaux GH Pellegrin: Centre Hospitalier Universitaire de Bordeaux Groupe hospitalier Pellegrin","correspondingAuthor":false,"prefix":"","firstName":"Jerome","middleName":"","lastName":"Harambat","suffix":""},{"id":378403582,"identity":"41e0069c-5d5d-4702-a9d3-a25b36119317","order_by":8,"name":"Emilija Golubovic","email":"","orcid":"","institution":"Klinicko-bolnicki centar Zvezdara Klinicko odeljenje za nefrologiju i metabolicke poremecaje","correspondingAuthor":false,"prefix":"","firstName":"Emilija","middleName":"","lastName":"Golubovic","suffix":""},{"id":378403583,"identity":"af1b714c-c844-424f-af0f-c6a0046f973a","order_by":9,"name":"Olivia Boyer","email":"","orcid":"","institution":"APHP: Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Olivia","middleName":"","lastName":"Boyer","suffix":""},{"id":378403584,"identity":"4ffcfb74-ce4d-4dbd-bf0d-3f63b93246e7","order_by":10,"name":"Massimo Di Maio","email":"","orcid":"","institution":"CHU Nimes: Centre Hospitalier Universitaire de Nimes","correspondingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"Di","lastName":"Maio","suffix":""},{"id":378403585,"identity":"a3030ecd-4c84-45f6-a7e2-7199a8f83ca9","order_by":11,"name":"Mathilde Caillez","email":"","orcid":"","institution":"APHM: Assistance Publique Hopitaux de Marseille","correspondingAuthor":false,"prefix":"","firstName":"Mathilde","middleName":"","lastName":"Caillez","suffix":""},{"id":378403586,"identity":"6dd145d3-47bc-4b4e-b5ef-466f56400e5f","order_by":12,"name":"Veronique Baudouin","email":"","orcid":"","institution":"APHP: Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Veronique","middleName":"","lastName":"Baudouin","suffix":""},{"id":378403587,"identity":"e49022cb-9599-47ca-bc73-f234373a8c32","order_by":13,"name":"Laure Chidler","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIie3PvwuCQBTA8SeBLleu53/xQiiC6G+5Q3CSfhBEg8NBa9Ac9Efc5Hwi1GJ7W05NDrq1lbUWalvDfXnj+/B4ADrdH9YDAorMAWwABNaGmG+CAI74hcCLoKpIq0zrHKscxzP3lEQ0C8fToSWMogxqCJmy+ID+KEr9FWVHfznaqo6zj2oIJZhUgwMVuMhFwuWFmZ1uM3mgu8tf5MHlNWtFFCIN+hkXqroCDYQEWP3iIb3cFhk7elymfFP7i22lbpGvJ2jvPBnfwwmXpyQuyhryLUP8tq/T6XS6j54WkFEk9WZZvwAAAABJRU5ErkJggg==","orcid":"","institution":"ADVICENNE","correspondingAuthor":true,"prefix":"","firstName":"Laure","middleName":"","lastName":"Chidler","suffix":""},{"id":378403588,"identity":"bbc3547f-c6be-4edc-bd6c-ad5a612885bb","order_by":14,"name":"Veronique Leblanc","email":"","orcid":"","institution":"ADVICENNE","correspondingAuthor":false,"prefix":"","firstName":"Veronique","middleName":"","lastName":"Leblanc","suffix":""},{"id":378403589,"identity":"48385bd8-aaa2-48e6-a985-d07dee20f3d6","order_by":15,"name":"Justine Bacchetta","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Justine","middleName":"","lastName":"Bacchetta","suffix":""}],"badges":[],"createdAt":"2024-08-22 11:52:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4957828/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4957828/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-03953-4","type":"published","date":"2025-08-13T15:58:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71747620,"identity":"cca7eb3b-8d68-4c6e-bd9d-98e8997fa65c","added_by":"auto","created_at":"2024-12-18 09:01:43","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":57898,"visible":true,"origin":"","legend":"\u003cp\u003eClinical design of Arena 1 program including B21CS and B22CS studies. The B21CS, Phase II/III study enrolled 37 patients and included three treatment periods: baseline/SoC, ADV7103 titration period, and fixed-dose ADV7103 period. A total of 30 patients from B21CS study entered the OLE B22CS study and 27 patients completed the study with an average of 6 years of treatment with ADV7103 (30 months for Slovakian and Serbian patients).\u003cu\u003e EoS\u003c/u\u003e, End of Study; \u003cu\u003eN\u003c/u\u003e, number of evaluated patients; \u003cu\u003eOLE,\u003c/u\u003e open label extension; \u003cu\u003eSoC,\u003c/u\u003eStandard of Care.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/e6523dc8874b360e867db92a.jpg"},{"id":71749080,"identity":"d5a0c31e-b555-4ef8-ba90-19e353ee8ac3","added_by":"auto","created_at":"2024-12-18 09:09:43","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":82807,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of mean height Z-score (a), weight Z-score (b), and BMI Z-score (c) data at baseline (M1) and EoF (post-hoc analysis, paired t-test). BMI, body mass index; EoF, End of Follow-up; M, Month.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/312f8c34f0b554a1aff1f36e.jpg"},{"id":71749079,"identity":"a11e9b14-ddb0-438a-ae67-85476e90105d","added_by":"auto","created_at":"2024-12-18 09:09:43","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":20508,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of mean height Z-score in patients with abnormal EAS (post-hoc analysis, repeated measure model adjusted on baseline) (n=6). EAS, estimated adult stature; EoS, End of Study; ET, early termination visit; M, month; n, number of evaluated patients.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/df3e4e8b2eda79e3c27b7ada.jpg"},{"id":71747627,"identity":"a466c75e-17c8-4428-9317-d2cf1aa403e3","added_by":"auto","created_at":"2024-12-18 09:01:43","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":51735,"visible":true,"origin":"","legend":"\u003cp\u003eMean plasma bicarbonate levels over time (descriptive analysis) and comparison EoF versus Baseline (post-hoc analysis, paired t-test). EoF, End of Follow-up; EoS, End of Study; M, month; N/n, number of evaluated patients; NS, non-significant; SD, standard deviation.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/f6a5d4fe3c3ac405c8ce3a00.jpg"},{"id":71749517,"identity":"d8d1125c-c29f-42ab-9a0f-11201b217323","added_by":"auto","created_at":"2024-12-18 09:17:43","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":53557,"visible":true,"origin":"","legend":"\u003cp\u003eMean plasma potassium levels over time (descriptive analysis) and comparison EoF versus Baseline (post-hoc analysis, paired t-test). EoF, End of Follow-up; EoS, End of Study; M, month; N/n, number of patients; NS, non-significant; SD, standard deviation.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/714364773ab26fd234492708.jpg"},{"id":71747625,"identity":"8f5af623-432c-412f-aaf4-348387625754","added_by":"auto","created_at":"2024-12-18 09:01:43","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":44392,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of mean lumbar spine BMD Z-score: mean change from baseline in all patients (post-hoc analysis, repeated measure model adjusted on baseline). BMD, bone mineral density; CI, confidence interval; ET, early termination visit; M, month; NS, non-significant; SD, standard deviation.\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/5da53584fb650f44d4bbe4ed.jpg"},{"id":71747621,"identity":"a20aadf3-c9f8-44d6-9b80-f6c6a3d17ada","added_by":"auto","created_at":"2024-12-18 09:01:43","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":35993,"visible":true,"origin":"","legend":"\u003cp\u003eMean lumbar spine BMD Z-score at baseline and EoF by pubertal status (post-hoc analysis, paired t-test). BMD, bone mineral density; EoF, End of Follow-up; n, number of patients.\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/b48561b838d55ec003ed1885.jpg"},{"id":89310672,"identity":"740c307b-7fd4-4b5b-aa79-dc2f0d328ed3","added_by":"auto","created_at":"2025-08-18 16:09:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1928908,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/13be0da5-9c1c-45a3-9679-65dd3581cb8a.pdf"},{"id":71747619,"identity":"d43b81d0-82f4-4d5f-a486-2e61209bdbc4","added_by":"auto","created_at":"2024-12-18 09:01:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":234931,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4957828/v1/f16242c61d1c5e31f821714c.docx"}],"financialInterests":"","formattedTitle":"Long-term clinical outcomes with an average of 6 years follow-up in dRTA patients treated with ADV7103 an oral twice-daily fixed and prolonged-release combination of potassium bicarbonate and potassium citrate (Sibnayal®).","fulltext":[{"header":"Key learning points","content":"\u003cp\u003e\u003cstrong\u003eWhat was known\u0026nbsp;\u003c/strong\u003e(maximum 50 words)\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe medical management of dRTA consists in the correction of metabolic acidosis to prevent long-term complications on growth, bone metabolism and kidney function. Growth and kidney function were shown to be correlated to metabolic control. Only half of patients had adequate metabolic control. More than 80% of adult patients had CDK\u0026nbsp;KDIGO\u0026ge;2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThis study adds\u0026nbsp;\u003c/strong\u003e(maximum 50 words)\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the first time, a long-term follow-up study provides safety and efficacy data of Sibnayal\u0026reg;, an alkali medication with long-lasting release allowing 2 intakes per day. This study supports a long-term adequate control of metabolic acidosis with Sibnayal\u0026reg;,\u0026nbsp;along with significant clinical outcomes on growth, kidney function and bone metabolism.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePotential impact\u0026nbsp;\u003c/strong\u003e(on practice or understanding, maximum 50 words)\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main challenge for physicians is to prevent long-term complications of dRTA by better controlling metabolic acidosis. Sibnayal\u0026reg; as an innovative prolonged-release alkalizing formulation with twice daily dosing, adapted for children, contributes to improving current medical management, clinical outcomes and quality of life of dRTA patients.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eDistal renal tubular acidosis (dRTA) is a rare tubular disease that can be inherited (with sensorineural hearing impairment in some genetic forms) and may also be acquired especially in adults\u003csup\u003e1\u003c/sup\u003e. The disorder is characterized by hyperchloremic metabolic acidosis with normal plasma anion gap, usually associated with hypokalemia. It induces negative effects on bone health and growth, such as stunting and failure to thrive, rickets in children, and osteomalacia in adults, which can be corrected with adequate control of metabolic acidosis\u003csup\u003e2\u0026ndash;5\u003c/sup\u003e. Hypercalciuria and hypocitraturia observed in dRTA lead to nephrocalcinosis, nephrolithiasis and chronic kidney disease (CKD)\u003csup\u003e2\u0026ndash;5\u003c/sup\u003e. Concerning inherited dRTA, recent European guidelines from the European Rare Kidney Disease Reference Network (ERKNet) and the European Society of Paediatric Nephrology (ESPN) have delineated the management of such patients\u003csup\u003e1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlkalizing therapy aims at normalizing bicarbonate levels to control metabolic acidosis and at preventing long-term complications\u003csup\u003e5\u003c/sup\u003e. The current Standard of Care (SoC) consists of alkalizing products, administered 3 to 6 times per day. The low gastrointestinal tolerability and bad taste of most alkali treatments, leading to poor adherence, explain that only half of patients have an adequate control of metabolic acidosis\u003csup\u003e5\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs an alternative, ADV7103, a prolonged-release granules and tasteless formulation of potassium citrate and potassium bicarbonate, allows a 12 hour-effect after a single dose, and is well tolerated\u003csup\u003e6\u003c/sup\u003e. In adult and pediatric patients with dRTA, ADV7103 has demonstrated an improved control of plasma bicarbonate levels, a surrogate marker of metabolic acidosis, over SoC treatments currently available, together with good acceptability and tolerability\u003csup\u003e7\u003c/sup\u003e. After 24 months of treatment with ADV7103, the safety, tolerability, efficacy, and compliance to treatment in these patients were maintained\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe aims of the B22CS study were to evaluate the long-term safety and efficacy of ADV7103, in pediatric and adults dRTA patients, with an average follow-up of 6 years.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eAs previously reported, all study patients had inherited dRTA\u003csup\u003e8\u003c/sup\u003e. Patients were divided into 4 age-groups: adults\u0026thinsp;\u0026ge;\u0026thinsp;18 years old, teenagers [12\u0026ndash;18 years old [, children [4\u0026ndash;12 years old [, and infants/toddlers [6 months-4 years old [. They were previously enrolled in a multicenter phase II/III trial, B21CS (EudraCT 2013-002988-25) having demonstrated the non-inferiority and then the superiority of ADV7103 as compared to SoC to maintain plasma bicarbonate level in the normal range\u003csup\u003e7\u003c/sup\u003e. These patients were then invited to participate in the multicenter, single-arm, open-label, follow-up B22CS study (EudraCT 2013-003828-36). At baseline visit (last visit of phase II/III trial), all patients were already treated by ADV7103. The study was first analyzed after a short follow-up period of 24 months\u003csup\u003e8\u003c/sup\u003e, and we present here the results of the long-term 6-year follow-up period with yearly visits (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All patients were included in the efficacy and safety analyses. Patients received doses of ADV7103 twice daily, adjusted to reach normal plasma bicarbonate levels, as defined in each local laboratory and assessed by each clinical Investigator.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSafety evaluation\u003c/h2\u003e \u003cp\u003eTreatment emergent adverse events (TEAEs) were recorded with their severity and relationship to the treatment. The number and percentage of patients presenting TEAEs by system organ class and preferred term, according to the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0), were calculated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAnthropometric and pubertal evaluations\u003c/h2\u003e \u003cp\u003eHeight (cm), weight (kg), and Body mass index (BMI) (kg/m\u003csup\u003e2\u003c/sup\u003e) were measured at yearly visits and expressed as Z-scores for age according to World Health Organization standards\u003csup\u003e9,10\u003c/sup\u003e. Height, weight and BMI Z-scores \u0026lt;-2.0 were considered for failure to thrive and stunting\u003csup\u003e11,12\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGenetic target height was determined from parents\u0026rsquo; final height, according to the American College of Medical Genetics practice guideline\u003csup\u003e13\u003c/sup\u003e. The Estimated Adult Stature (EAS) was calculated at baseline, Month 24, Month 48 and EoS as the height at Tanner stage 5 or the extrapolated height at 19 years (considering the Z-score at the time of evaluation). The EAS was considered normal when it was within the range target height\u0026thinsp;\u0026plusmn;\u0026thinsp;10 cm for boys and target height\u0026thinsp;\u0026plusmn;\u0026thinsp;9 cm for girls\u003csup\u003e14\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePubertal maturity was evaluated according to Tanner stage standard tables containing the age percentiles for each stage in the reference population\u003csup\u003e15\u0026ndash;17\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAssessments of tubular damages and kidney function\u003c/h2\u003e \u003cp\u003eThe following parameters were measured in local laboratories: plasma bicarbonate, kalemia and creatininemia, urinary pH (evaluated by glass electrode pH-meter), ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR), urine calcium/creatinine ratio (UCa/UCr), urine citrate/creatinine ratio (UCi/UCr), and urine calcium/citrate ratio (UCa/UCi). Normal ranges were provided from published data depending on patient age and gender\u003csup\u003e18\u0026ndash;21\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe estimated glomerular filtration rate (eGFR) was calculated according to the CKiD Under 25 (CKiDU-25) Eq.\u0026nbsp;2\u003csup\u003e2\u003c/sup\u003e. Decreased kidney function was considered when eGFR was \u0026lt;\u0026thinsp;90 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, with CKD stages according to Kidney Disease Improving Global Outcomes guidelines\u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe risk of lithogenesis was evaluated with a threshold of UCa/UCi above 3.0 mmol/mmol and UCa/UCr above normal range according to age\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCrystalluria analyses were performed in local laboratories with focus on amorphous carbonated calcium phosphate (ACCP) crystals that are specific to dRTA. Crystalluria was evaluated by the examination of a well-homogenized fresh morning urine sample set in a Malassez cell by light microscopy.\u003c/p\u003e \u003cp\u003eThe presence or absence of nephrocalcinosis (without grading) and nephrolithiasis was assessed at each visit mainly by kidney ultrasounds and possibly computed tomography (CT)-scan when it was available for adult patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBone biomarkers assessment\u003c/h2\u003e \u003cp\u003eRickets and osteomalacia were determined following investigator\u0026rsquo;s clinical judgement, based on clinical signs (diffuse bone and joint pain, myalgia, muscle weakness, abnormal posture, abnormal stature, walking difficulty), radiologic signs (abnormal bone aspect, bone deformation, pseudofracture) and biochemical signs (abnormal values of plasma bone alkaline phosphatases (bALPs), calcium and phosphate). Bone and phosphate/calcium metabolism biomarkers were assessed up to Month 48 in a central laboratory for 1-25-dihydroxy-vitamin D (1-25-OH-vit-D, normal range: 69\u0026ndash;200 pmol/L), bALPs, (normal values depending on age and gender), parathyroid hormone (PTH, normal range: 5.5\u0026ndash;38.4 ng/L). In contrast, 25-hydroxy-vitamin D (25-OH-vit-D), plasma phosphate and calcium were performed in local laboratories. Plasma phosphate and bALPs were expressed as Z-scores for age and gender\u003csup\u003e25,26\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBone Mineral Density (BMD, g/cm\u003csup\u003e2\u003c/sup\u003e) was measured yearly in three skeletal regions (lumbar spine, hip and whole body) using dual-energy X-ray absorptiometry (DXA) and expressed as Z-score. Only lumbar spine area results are presented as this is the only relevant skeletal area for both pediatric and adult populations. Values of Z-score \u0026lt;-2.0 SD were considered below the normal range according to the recommendations of the International Society for Clinical Densitometry\u003csup\u003e27\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of compliance to treatment\u003c/h2\u003e \u003cp\u003ePatients were asked to return their unused treatment units (sachets) to calculate the proportion of treatment that had been taken versus what should have been taken according to study protocol. When patients did not return unused sachets, compliance was estimated by questioning the patient and/or his/her family while considering laboratory results. In case of doubt, treatment was considered as not taken by the patient. Treatment compliance was qualified \u0026ldquo;poor\u0026rdquo; when compliance rate was \u0026lt;\u0026thinsp;50%, \u0026ldquo;average\u0026rdquo; at 50 to \u0026lt;\u0026thinsp;75%, \u0026ldquo;good\u0026rdquo; at 75 to 90%, and \u0026ldquo;excellent\u0026rdquo; at \u0026gt;\u0026thinsp;90%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe final data analysis included data collected from November 2014 to the end of the study dated October 2021. All patients receiving at least one dose of ADV7103 and with at least one efficacy assessment were included in the efficacy analysis set.\u003c/p\u003e \u003cp\u003eSafety and efficacy data and their change from baseline (when appropriate) were summarized over time using descriptive statistics by age group (according to age at baseline) or considering pooled pediatric patients and the overall patient population.\u003c/p\u003e \u003cp\u003eThe originally planned statistical analyses B22CS studies were mainly descriptive from baseline to End of Study (EoS, last visit in the study), except for a repeated measures model on change from baseline adjusted on baseline for lumbar spine BMD Z-scores. All other statistical tests and associated figures were performed as post-hoc analyses.\u003c/p\u003e \u003cp\u003eFor these post-hoc analyses, an End of Follow-up (EoF) value corresponding to the last available patient value for each parameter was computed. The EoF values were compared to baseline values, to assess the evolution of parameters between first and last measurements. The value measured during the EoS visit was used when assessing the evolution of a parameter over time throughout the study.\u003c/p\u003e \u003cp\u003eData were described as proportions or mean (\u0026plusmn;\u0026thinsp;standard deviation, \u0026plusmn;SD) according to the nature of the parameter. To compare two quantitative values (mean at baseline versus EoF for instance), a paired Student\u0026rsquo;s t-test or a Wilcoxon signed-rank test was used depending on if the data is normally distributed or not, respectively (normality was assessed using Skewness and Kurtosis values as well as graphical checks). When proportions were compared (number of patients in normal range at baseline versus EoF for instance), a McNemar\u0026rsquo;s test (when two categories are involved) or a symmetry test (when more than two categories are involved) was used. To evaluate the evolution of a parameter over time, a repeated measures model on change from baseline, adjusted on baseline, was performed. Values of mean least squares and 95% confidence interval (CI) were reported for the difference between each visit and baseline. All statistical tests were two-sided and carried out at the 5% level of significance. These tests were performed for exploratory purposes only and no adjustment for multiplicity was performed. Most tests are displayed with a graphical representation.\u003c/p\u003e \u003cp\u003eAnalyses were performed using SAS\u0026reg; software, Version 9.4 (SAS Institute Inc., Cary, NC, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eMain data of B22CS patients are summarized in \u003cstrong\u003eTable 1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients\u0026rsquo; characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 30 patients (6 adults, 8 teenagers, 13 children and 3 infants), all presenting with inherited dRTA, entered the long-term study, 27 of whom had data collected beyond Month 30 (\u003cstrong\u003eFigure 1\u003c/strong\u003e). The mean age (years) of patients were 10.6\u0026plusmn;6.0 (min-max: 2-21) at baseline and 16.4\u0026plusmn;6.0 (min-max: 7.8-28.0) at EoF, respectively. Mean and median durations (years) of follow-up were 5.8\u0026plusmn;1.3 and 6.3 (min-max:1.1-6.8), respectively (\u003cstrong\u003eTable 1\u003c/strong\u003e). A total of 22 patients (73%) underwent genetic analysis, that found pathogenic variants in 21 patients (ATP6V0A4, N=9, ATP6V1B1 N=12) while the genetic mutation was not identified for 1 patient. Hearing impairment was reported in 20 patients, including all 6 adults.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSafety\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOver the course of the study, a total of 309 TEAEs were experienced by 29 patients. The most frequently reported TEAEs were vitamin D deficiency (13 patients, 43.3%), hypokalemia (8 patients, 26.7%), iron deficiency (7 patients, 23.3%) and decreased appetite (2 patients, 6.7%). Of all TEAEs, 13 (4%) TEAEs were related to treatment, reported in 6 patients (20%). The majority of these related TEAEs were gastrointestinal disorders (N=11), reported in 5 patients (16.7%), and were of mild or moderate intensity, resolving without discontinuation of the treatment. No serious adverse events related to the treatment were reported (\u003cstrong\u003eSupplemental\u003c/strong\u003e \u003cstrong\u003eTable S1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eChanges in pubertal maturity and growth\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePubertal maturity was normal in most pediatric patients throughout the study (\u0026gt;90%). Overall, 11/23 pediatric patients (48%) (including 7/8 teenagers [87%]) reached Tanner Stage 5 by EoS.\u003c/p\u003e\n\u003cp\u003eMean height Z-score significantly increased between baseline and EoF (-0.6\u0026plusmn;1.0 to ‑0.3\u0026plusmn;1.0, p=0.03) (\u003cstrong\u003eFigure 2A\u003c/strong\u003e) (descriptive analysis by age group and in all patients in \u003cstrong\u003eSupplemental Figure S1\u003c/strong\u003e), whilst mean weight and BMI Z-scores remained stable (p=NS) (\u003cstrong\u003eFigures 2B, 2C\u003c/strong\u003e) (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition, the increase in mean height Z-score overtime was significantly greater in patients with abnormal EAS at baseline (N=6) as compared to patients with normal EAS at baseline (N=20) (p\u0026lt;0.001) (\u003cstrong\u003eFigure 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eOverall, most patients had a normal EAS at baseline. The proportion of patients with a normal EAS remained stable throughout the study from 20/26 patients (77%) at baseline to 21/26 patients (81%) at EoF, (p=NS) (\u003cstrong\u003eTable 1\u003c/strong\u003e). Among the 6 patients with abnormal EAS at baseline, 4 patients reached a normal EAS at EoF. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEvolution of\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003etubular damages and kidney function\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean plasma bicarbonate levels remained stable throughout the 6-year follow-up from 22.0\u0026plusmn;3.2 at baseline to 22.6\u0026plusmn;2.5 mmol/L at EoF, p=NS (\u003cstrong\u003eFigure 4\u003c/strong\u003e). When only considering patients with blood samples taken before study treatment intake, the same evolution profile was shown. Mean plasma potassium levels were also stable over the study duration, from 3.8\u0026plusmn;0.5 at baseline to 3.7\u0026plusmn;.0.4 mmol/L at EoF, p=NS (\u003cstrong\u003eFigure 5\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMean eGFR values remained stable over time, from\u0026nbsp;105\u0026plusmn;17\u0026nbsp;at baseline to\u0026nbsp;104\u0026plusmn;20 mL/min/1.73 m\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eat EoF, p=NS (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAmong 23 patients with an eGFR measurement, 20 patients had CKD stage 1 at baseline (87%) and 17 patients (74%) at EoF. In addition, 3 patients had CKD stage 2 at baseline (13%) and 6 patients at EoF (26%). There was no statistical difference in CKD stages breakdown between baseline and EoF (p=NS) and no patient reached CKD stage 3 to 5 during the study (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eUrinary ratios associated with the risk of nephrolithiasis/nephrocalcinosis (UCa/UCr, UCi/UCr and UCa/UCi) were not significantly different between baseline and EoF (p=NS)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eThe percentage of patients with positive crystalluria tended to decrease (53% at baseline and 35% at EoF, p=NS). There was no significant increase in the occurrence of ACCP crystals, 47% patients at baseline versus 35% patients at EoF, p=NS. (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eThe proportion of patients with urinary pH in the 7-8 range was stable across the study (70% at baseline and EoF). The proportion of patients with urine pH \u0026lt;7 or \u0026gt;8 respectively varied from 9% and 22% at baseline to 0% and 30% at EoF, p=NS. So, there was no impact on ACCP crystals presence despite some patients with urinary pH \u0026gt;8 (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eKidney ultrasounds / CT scans\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe number of patients presenting nephrolithiasis increased from 6/28 patients (21%) at baseline to 11/28 patients (39%) at EoF, p=NS. Only one case of surgical procedure for kidney stone removal during the study course was reported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNephrocalcinosis was present in 25/28 of patients (89%) at baseline and in 26/28 patients (93%) at EoF, p=NS. Nephrocalcinosis appeared in 3 patients during the study and 2 patients with nephrocalcinosis at baseline had no more nephrocalcinosis detected by imaging at EoF.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEvolution of bone biomarkers\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the adults were diagnosed with osteomalacia throughout the study. Rickets was reported in 1 infant at baseline and 4 pediatric patients at Month 36 (2 children and 2 teenagers). From Month 60, rickets were no longer reported in patients.\u003c/p\u003e\n\u003cp\u003ePTH levels remained in the normal range over 48 months: 15.6 \u0026plusmn; 8.2 to 16.6 \u0026plusmn; 6.6 ng/L at baseline and Month 48, respectively, p=NS (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eConcerning bALP levels, most patients (from 75% to 96%, according to the study visit) had levels in the normal range over 48 months and mean bALP Z-score was maintained from baseline to Month 48 in the overall population, p=NS. Mean serum phosphate Z-score significantly decreased over 48 months from -0.7\u0026plusmn;0.7 to -1.4\u0026plusmn;1.1, p=0.005 (\u003cstrong\u003eSupplemental\u003c/strong\u003e \u003cstrong\u003eFigure S2\u003c/strong\u003e). Mean TmP/GFR also significantly decreased from 1.5\u0026plusmn;0.2 at baseline to 1.3\u0026plusmn;0.3 mmol/L at EoF, p=0.001. Mean circulating calcium levels slightly increased from 2.38\u0026plusmn;0.10 at baseline to 2.42\u0026plusmn;0.08 mmol/L at EoF, p=0.048. Mean serum 25-OH-vit-D levels were low during the study (55.0\u0026plusmn;33.7 at baseline and 51.0\u0026plusmn;19.2 nmol/L at Month 48) while mean serum 1-25-OH-vit-D levels were in the normal ranges (164.6\u0026plusmn;54.1 at baseline and 158.6\u0026plusmn;36.3 pmol/L at Month 48), p=NS (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEvolution of bone mineral density\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA significant improvement in mean lumbar spine BMD Z-score was observed from baseline (-1.1\u0026plusmn;1.0) to EoF (-0.8\u0026plusmn;1.0), p=0.005. Lumbar spine BMD Z-scores were normal in most patients from baseline (71%) to EoF (87%) (\u003cstrong\u003eTable 1\u003c/strong\u003e). Over the study duration, lumbar spine BMD Z-score evolution was not statistically significant, while the change from baseline to each yearly visit was statistically significant using the same statistical test (\u003cstrong\u003eFigure 6\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMean lumbar spine BMD Z-score varied according to patients\u0026rsquo; pubertal status with a significant improvement from baseline to EoF in pre-and post-pubertal patients while it was maintained in patients in pubertal phase: -1.2\u0026plusmn;1.3 at baseline and -0.5\u0026plusmn;0.9 at EoF, p=0.035 in pre-pubertal patients, -1.0\u0026plusmn;1.0 at baseline and -0.4\u0026plusmn;0.8 at EoF, p\u0026lt;0.001 in post-pubertal patients and -1.2\u0026plusmn;0.9 at baseline and -1.3\u0026plusmn;1.0 at EoF, p=NS in pubertal patients (\u003cstrong\u003eFigure 7\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eADV7103 dose and compliance\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall mean dose prescribed evolved from 3.4\u0026plusmn;1.7 at baseline to 2.3\u0026plusmn;1.1 mEq/kg/d at EoS (\u003cstrong\u003eSupplemental\u003c/strong\u003e \u003cstrong\u003eFigure S3\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe compliance\u0026nbsp;rate was good or excellent in 58% to 83% patients, depending on the\u0026nbsp;time considered.\u0026nbsp;At EoS, compliance rate was good to excellent for 16/27 patients (60%). Compliance was lower in teenagers whose compliance rate was poor at EoS for 4/7 teenagers (57%) compared to 0/5 adults, 1/12 children (8%) and 0/3 infants (\u003cstrong\u003eSupplemental\u003c/strong\u003e \u003cstrong\u003eFigure S4\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn dRTA patients, metabolic acidosis control is the main goal to prevent short and long-term complications of the disease\u003csup\u003e28\u0026ndash;31\u003c/sup\u003e. This objective can be highly challenging to attain for patients carrying H\u003csup\u003e+\u003c/sup\u003e-ATPase variants\u003csup\u003e32,33\u003c/sup\u003e, as it is the case in 85% of the present population. Thus, the current challenge for pediatric and adult nephrologists in dRTA is to improve the proportion of patients displaying adequate metabolic control and to have robust outcome data to prevent long-term complications, especially on growth, bone metabolism and kidney function.\u003c/p\u003e \u003cp\u003eFew long-term outcome data have been reported to date. A collaborative work between ERKNet and the European Renal Association collecting data from a large European multinational cohort of dRTA patients is ongoing\u003csup\u003e34\u003c/sup\u003e. Lopez-Garcia et al. reported data from a large cohort of 340 patients (29 countries) with a median age at last follow-up of 11.0 (0.0\u0026ndash;70.0) years\u003csup\u003e5\u003c/sup\u003e. The median prescribed dose of alkali treatment was 1.9 mEq/kg/d. Only 51% of patients achieved adequate metabolic control under alkali treatment, keeping in mind that higher bicarbonate plasma levels were associated with better growth and kidney function.\u003c/p\u003e \u003cp\u003eADV7103 is a prolonged-release formulation of potassium citrate and potassium bicarbonate with a twice daily administration, approved by the European Medical Agency in April 2021 in the treatment of patients with inherited or acquired dRTA, aged one year and older. ADV7103 has been developed over the last decade from a collaboration between French physicians and a pharmaceutical company in response to a direct request from clinicians. A superiority to maintain plasma bicarbonate levels compared to SoC was demonstrated in a short-term study\u003csup\u003e7\u003c/sup\u003e. In addition, over 24 months, a sustained control of metabolic acidosis was shown together with a good treatment acceptability and an improvement of Quality of Life (QoL) (quantitative assessment)\u003csup\u003e8\u003c/sup\u003e. In addition, a long-term QoL analysis (qualitative assessment) was done using semi-structured interviews with patients and/or parents after at least 48 months of treatment, with an average of 5 years. Results were previously published and showed a high level of patients/parents\u0026rsquo; satisfaction\u003csup\u003e35\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe good safety profile over 24 months previously published was confirmed over 6 years and no additional safety or tolerability concerns associated to the use of ADV7103 were raised. No pattern of increasing adverse events (treatment-related or not) was observed with increasing duration of exposure to the treatment.\u003c/p\u003e \u003cp\u003eThe present study also confirms the long-term efficacy of ADV7103 to maintain normal plasma bicarbonate levels. A total of 73% of patients indeed displayed normal plasma bicarbonate after an average 6-year follow-up. As shown in Lopez-Garcia\u0026rsquo;s cohort\u003csup\u003e5\u003c/sup\u003e, adequate metabolic control is significantly linked with growth improvement. With ADV7103, mean height Z-score significantly increased without BMI increase. The improvement of height in the adult group may be explained by the mean age of this group at inclusion (19.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1 years).\u003c/p\u003e \u003cp\u003eThe most significant growth improvement was observed in patients with abnormal EAS at baseline. Our data confirmed that an adequate metabolic acidosis control allowed a better growth prognosis for patients including young adult patients.\u003c/p\u003e \u003cp\u003eKidney function in patients with dRTA declines significantly earlier than in general population, CKD affecting indeed at least a third of dRTA patients from the second decade of life\u003csup\u003e3\u0026ndash;5,32\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhen considering the comparable age patient subset from Lopez-Garcia\u0026rsquo;s cohort\u003csup\u003e5\u003c/sup\u003e, (n\u0026thinsp;=\u0026thinsp;167, mean age: 15.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0 years): 45.5% of their patients were CKD stage\u0026thinsp;\u0026ge;\u0026thinsp;2 versus 26.0% in our study. We observe a noticeable improvement of eGFR in our study. For the first time, we report a promising stabilization of kidney function during the long-term observation period in dRTA patients receiving ADV7103.\u003c/p\u003e \u003cp\u003eIn our study, and as already reported in retrospective studies\u003csup\u003e3\u0026ndash;5,32,36\u003c/sup\u003e, nephrocalcinosis was reported in most patients at baseline, leading to difficult interpretation of ADV7103 effect on this parameter. Over the study duration, calciuria and citraturia were maintained in normal range, in 90% and 45% of patients, respectively (stable risk of lithogenesis). So, we could expect a decrease in intra-tubular crystallization and of calcium deposits in the kidney which could protect renal function\u003csup\u003e37,38\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNephrolithiasis was stable among patients between baseline and EoF. There was only one case of kidney stone removal during the 6-year study, while this event has been reported as the most frequent during the dRTA patient management\u003csup\u003e39\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAn additional major concern for physicians is the bone and mineral management of dRTA patients as there is few published data about the correction of bone parameters with alkali treatments. In a small cohort of adult patients with secondary dRTA (N\u0026thinsp;=\u0026thinsp;14), Domrongkitchaiporn et al. reported osteopenia, fractures and significantly low BMD\u003csup\u003e40,41\u003c/sup\u003e. After one year of alkali therapy, they showed a significant increase in BMD and a normalization of bone formation rate. They hypothesized that chronic metabolic acidosis results in a suppression of bone formation and resorption, as previously shown in experimental papers demonstrating a deleterious effect of acidosis both on osteoblastic differentiation and osteoclastic differentiation/activity\u003csup\u003e42\u0026ndash;44\u003c/sup\u003e. In our study, most bone markers remained in the normal range, specifically bALPs, while a significant decrease in mean serum phosphate Z-score and TmP/GFR was observed. This suggests an increase in bone mass, improvement of bone modeling rate and mineralization. This is supported by a continuous and significant improvement of lumbar spine BMD Z-score, expressed as change from baseline. It can nevertheless also be argued that serum phosphate levels decrease with age, and particularly during childhood and adolescence, but the data were analyzed using standardization for age to avoid this age-specific effect.\u003c/p\u003e \u003cp\u003eThese positive long-term effects of ADV7103 are linked to its efficacy but also likely to the good compliance to treatment maintained throughout the follow-up except in teenagers where high prevalence of poor adherence to chronic treatments is well-known\u003csup\u003e45\u003c/sup\u003e. This age group is known to require specific multidisciplinary teams, including social workers, psychologists, specific transition programs\u003csup\u003e46\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe main limitation of our study was the absence of a direct comparator during follow-up. However, a long-term randomized controlled trial was not considered feasible (nor ethical) in a rare disease such as dRTA. The set-up of the European dRTA registry will further consolidate the long-term evolution of dRTA patients based on alkali treatments\u003csup\u003e34\u003c/sup\u003e. Another limitation is the absence of morpho-constitutional analysis of stones and not enough CT imaging performed to detect and follow nephrocalcinosis and nephrolithiasis.\u003c/p\u003e \u003cp\u003eIn conclusion, treatment with ADV7103 ensures the first long-term evidence of metabolic acidosis control and prevention of long-term dRTA complications with a good safety and tolerability profile. ADV7103 significantly improves growth and lumbar spine BMD in pediatric and young adult dRTA patients. Most importantly, kidney function is preserved for a significant long period (6 years on average). Overall, these results contribute to improving the management and outcomes of this orphan disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by regional independent ethics committees (CPP sud-est II; \u0026nbsp; clinical center of ni\u0026scaron;, ethics committee, Ni\u0026scaron;; Etick\u0026aacute; komisia Detsk\u0026aacute; fakultn\u0026aacute; nemocnica s poliklinikou Bratislava, Bratislava) and national regulatory health authorities and conducted in accordance with Good Clinical Practice and the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all adult patients, and from the parents or legal guardians of all children. When possible, the assent from pediatric patients themselves was also obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from ADVICENNE, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of ADVICENNE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026rsquo;s statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Bertholet-Thomas received travel and speaker fees from Advicenne.\u003c/p\u003e\n\u003cp\u003eJ. Bacchetta received speaker fees from Advicenne.\u003c/p\u003e\n\u003cp\u003eL. Chidler and V. Leblanc are Advicenne\u0026rsquo;s employees.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Advicenne.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026lsquo; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAurelia Bertholet-Thomas: Global concept of the clinical trial, patient enrollment and management, data collection and interpretation, manuscript writing and critical review of the manuscript.\u003c/p\u003e\n\u003cp\u003eJustine Bacchetta: Patient enrollment and management, data collection and interpretation and critical review of the manuscript.\u003c/p\u003e\n\u003cp\u003eJulie Bernardor: Data interpretation and critical review of data.\u003c/p\u003e\n\u003cp\u003eAur\u0026eacute;lie De Mul: Data interpretation and critical review of data.\u003c/p\u003e\n\u003cp\u003eGwena\u0026euml;lle Roussey-Kesler, Ludmila Podracka, Robert Novo, Fran\u0026ccedil;ois Nobili, Bertrand Knebelmann, J\u0026eacute;r\u0026ocirc;me Harambat, Emilija Golubovic, Olivia Boyer, Massimo Di Maio, Mathilde Cailliez, and V\u0026eacute;ronique Baudouin: Patient enrollment and management, data collection and critical review of the manuscript.\u003c/p\u003e\n\u003cp\u003eLaure Chidler, V\u0026eacute;ronique Leblanc: Critical review of data, manuscript writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication :\u0026nbsp;\u003c/strong\u003eAll authors consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the Investigators of B22CS study and their corresponding Clinical Investigation Centers for their involvement in conducting the clinical trial.\u003c/p\u003e\n\u003cp\u003eWe thank Camilo Lopez Garcia, MD and Detlef B\u0026ouml;ckenhauer, MD, PhD for the agreement of use of their data in the discussion of this article.\u003c/p\u003e\n\u003cp\u003eThe authors thank Advicenne for the initiation of this clinical program.\u003c/p\u003e\n\u003cp\u003eThis work benefited from the collaboration of members of French Orphan Kidney Disease Network (ORKiD), of the European Rare Kidney Disease Reference Network (ERKNet) and of the European Reference Network for Rare Bone Diseases (ERN BOND).\u003cstrong\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTRIAL REGISTRATION NUMBER\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegistered as EudraCT 2013-003828-36 on September 03, 2013.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTrepiccione F, Walsh SB, Ariceta G, et al. Distal renal tubular acidosis: ERKNet/ESPN clinical practice points. \u003cem\u003eNephrol Dial Transplant\u003c/em\u003e. 2021;36(9):1585-1596. doi:10.1093/ndt/gfab171.\u003c/li\u003e\n\u003cli\u003eVall\u0026eacute;s PG, Batlle D. Hypokalemic Distal Renal Tubular Acidosis. \u003cem\u003eAdv Chronic Kidney Dis\u003c/em\u003e. 2018;25(4):303-320. doi:10.1053/j.ackd.2018.05.003.\u003c/li\u003e\n\u003cli\u003eG\u0026oacute;mez-Conde S, Garc\u0026iacute;a-Casta\u0026ntilde;o A, Aguirre M, et al. Molecular aspects and long-term outcome of patients with primary distal renal tubular acidosis. \u003cem\u003ePediatr Nephrol\u003c/em\u003e. 2021;36(10):3133-3142. doi:10.1007/s00467-021-05066-z.\u003c/li\u003e\n\u003cli\u003eForero-Delgadillo JM, Gil-Pe\u0026ntilde;a H, Alonso-Varela M, Santos F; RenalTube Group. Kidney function in patients with primary distal renal tubular acidosis. \u003cem\u003ePediatr Nephrol\u003c/em\u003e. 2021;36(7):1931-1935. doi:10.1007/s00467-021-05068-x.\u003c/li\u003e\n\u003cli\u003eLopez-Garcia SC, Emma F, Walsh SB, et al. Treatment and long-term outcome in primary distal renal tubular acidosis. \u003cem\u003eNephrol Dial Transplant\u003c/em\u003e. 2019;34(6):981-991. doi:10.1093/ndt/gfy409.\u003c/li\u003e\n\u003cli\u003eGuittet C, Roussel-Maupetit C, Manso-Silv\u0026aacute;n MA, Guillaumin F, Vandenhende F, Granier LA. Innovative prolonged-release oral alkalising formulation allowing sustained urine pH increase with twice daily administration: randomized trial in healthy adults. \u003cem\u003eSci Rep\u003c/em\u003e. 2020;10(1):13960. Published 2020 Aug 18. doi:10.1038/s41598-020-70549-2.\u003c/li\u003e\n\u003cli\u003eBertholet-Thomas A, Guittet C, Manso-Silv\u0026aacute;n MA, et al. Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments. \u003cem\u003ePediatr Nephrol\u003c/em\u003e. 2021;36(1):83-91. doi:10.1007/s00467-020-04693-2.\u003c/li\u003e\n\u003cli\u003eBertholet-Thomas A, Guittet C, Manso-Silv\u0026aacute;n MA, et al. Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis. \u003cem\u003ePediatr Nephrol\u003c/em\u003e. 2021;36(7):1765-1774. doi:10.1007/s00467-020-04873-0.\u003c/li\u003e\n\u003cli\u003eWHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. \u003cem\u003eActa Paediatr Suppl\u003c/em\u003e. 2006;450:76-85. doi:10.1111/j.1651-2227.2006.tb02378.x.\u003c/li\u003e\n\u003cli\u003ede Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. \u003cem\u003eBull World Health Organ\u003c/em\u003e. 2007;85(9):660-667. doi:10.2471/blt.07.043497.\u003c/li\u003e\n\u003cli\u003eWHO Multicentre Growth Reference Study Group. Assessment of differences in linear growth among populations in the WHO Multicentre Growth Reference Study. \u003cem\u003eActa Paediatr Suppl\u003c/em\u003e. 2006;450:56-65. doi:10.1111/j.1651-2227.2006.tb02376.x.\u003c/li\u003e\n\u003cli\u003eWang Y, Chen H-J. Use of percentiles and Z-scores in anthropometry. In: Preedy VR, ed. \u003cem\u003eHandbook of anthopometry: Physical measures of human form in health and disease\u003c/em\u003e. Springer. 2012: 29-48. doi:10.1007/978-1-4419-1788-1_2.\u003c/li\u003e\n\u003cli\u003eSeaver LH, Irons M; American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee. ACMG practice guideline: genetic evaluation of short stature. \u003cem\u003eGenet Med\u003c/em\u003e. 2009;11(6):465-470. doi:10.1097/GIM.0b013e3181a7e8f8.\u003c/li\u003e\n\u003cli\u003eZhang Z, Shoff SM, Lai HJ. Incorporating genetic potential when evaluating stature in children with cystic fibrosis. \u003cem\u003eJ Cyst Fibros\u003c/em\u003e. 2010;9(2):135-142. doi:10.1016/j.jcf.2010.01.003.\u003c/li\u003e\n\u003cli\u003eMarshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. \u003cem\u003eArch Dis Child\u003c/em\u003e. 1969;44(235):291-303. doi:10.1136/adc.44.235.291.\u003c/li\u003e\n\u003cli\u003eMarshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. \u003cem\u003eArch Dis Child\u003c/em\u003e. 1970;45(239):13-23. doi:10.1136/adc.45.239.13.\u003c/li\u003e\n\u003cli\u003eWHO Sexual and Reproductive Health and Research. The sexual and reproductive health of younger adolescents in developing countries: research issues in developing countries. 2011.\u003c/li\u003e\n\u003cli\u003eMatos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. \u003cem\u003eJ Pediatr\u003c/em\u003e. 1997;131(2):252-257. doi:10.1016/s0022-3476(97)70162-8.\u003c/li\u003e\n\u003cli\u003eFrey J, Daudon M, Raby N, et al. Valeur s\u0026eacute;m\u0026eacute;iologique des param\u0026egrave;tres biochimiques urinaires [Clinical value of urinary biochemical parameters]. \u003cem\u003eAnn Biol Clin (Paris)\u003c/em\u003e. 2001;59(1):13-25.\u003c/li\u003e\n\u003cli\u003eKirejczyk JK, Porowski T, Konstantynowicz J, et al. Urinary citrate excretion in healthy children depends on age and gender. \u003cem\u003ePediatr Nephrol\u003c/em\u003e. 2014;29(9):1575-1582. doi:10.1007/s00467-014-2806-\u003c/li\u003e\n\u003cli\u003eDerain Dubourg L, Aurelle M, Chardon L, Flammier S, Lemoine S, Bacchetta J. Tubular phosphate handling: references from child to adulthood in the era of standardized serum creatinine. \u003cem\u003eNephrol Dial Transplant\u003c/em\u003e. 2022;37(11):2150-2156. doi:10.1093/ndt/gfab331.\u003c/li\u003e\n\u003cli\u003ePierce CB, Mu\u0026ntilde;oz A, Ng DK, Warady BA, Furth SL, Schwartz GJ. Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. \u003cem\u003eKidney Int\u003c/em\u003e. 2021;99(4):948-956. doi:10.1016/j.kint.2020.10.047.\u003c/li\u003e\n\u003cli\u003eGroup Kidney Disease: Improving Global Outcomes (KDIGO). Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. \u003cem\u003eKidney Int.\u003c/em\u003e Supplements. 2013;3(1):1-150.\u003c/li\u003e\n\u003cli\u003eParent X, Boess G, Brignon P. Lithiase oxalocalcique. Relation entre facteurs de risque biochimiques et phase cristalline du calcul. \u003cem\u003eProg Urol.\u003c/em\u003e 1999;9:1051-1056.\u003c/li\u003e\n\u003cli\u003eArdeshirpour L, Cole DE, Carpenter TO. Evaluation of bone and mineral disorders. \u003cem\u003ePediatr Endocrinol Rev\u003c/em\u003e. 2007;5 Suppl 1:584-598.\u003c/li\u003e\n\u003cli\u003eCavalier E, Rozet E, Carlisi A, et al. Analytical validation of serum bone alkaline phosphatase (BAP OSTASE) on Liaison. \u003cem\u003eClin Chem Lab Med\u003c/em\u003e. 2010;48(1):67-72. doi:10.1515/CCLM.2010.019.\u003c/li\u003e\n\u003cli\u003eSchousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. \u003cem\u003eJ Clin Densitom\u003c/em\u003e. 2013;16(4):455-466. doi:10.1016/j.jocd.2013.08.004.\u003c/li\u003e\n\u003cli\u003eGreen J, Maor G. Effect of metabolic acidosis on the growth hormone/IGF-I endocrine axis in skeletal growth centers. \u003cem\u003eKidney Int\u003c/em\u003e. 2000;57(6):2258-2267. doi:10.1046/j.1523-1755.2000.00086.x.\u003c/li\u003e\n\u003cli\u003eArnett TR. Acidosis, hypoxia and bone. \u003cem\u003eArch Biochem Biophys\u003c/em\u003e. 2010;503(1):103-109. doi:10.1016/j.abb.2010.07.021.\u003c/li\u003e\n\u003cli\u003eBrown DD, Roem J, Ng DK, et al. Low Serum Bicarbonate and CKD Progression in Children. \u003cem\u003eClin J Am Soc Nephrol\u003c/em\u003e. 2020;15(6):755-765. doi:10.2215/CJN.07060619.\u003c/li\u003e\n\u003cli\u003eBajpai A, Bagga A, Hari P, Bardia A, Mantan M. Long-term outcome in children with primary distal renal tubular acidosis. \u003cem\u003eIndian Pediatr\u003c/em\u003e. 2005;42(4):321-328.\u003c/li\u003e\n\u003cli\u003ePalazzo V, Provenzano A, Becherucci F, et al. The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis. \u003cem\u003eKidney Int\u003c/em\u003e. 2017;91(5):1243-1255. doi:10.1016/j.kint.2016.12.017.\u003c/li\u003e\n\u003cli\u003eGiglio S, Montini G, Trepiccione F, Gambaro G, Emma F. Distal renal tubular acidosis: a systematic approach from diagnosis to treatment. \u003cem\u003eJ Nephrol\u003c/em\u003e. 2021;34(6):2073-2083. doi:10.1007/s40620-021-01032-y.\u003c/li\u003e\n\u003cli\u003eGiaccari M, Haffner D, Schaefer F et al. First interim analysis of the international distal renal tubular acidosis registry \u003cem\u003eNephrol Dial Transplant.\u003c/em\u003e 2023;38 Vol. 38; pp. I4 - I4.Oxford University Press (OUP) (Abstract 4989).\u003c/li\u003e\n\u003cli\u003eAcquadro M, Marrel A, Manso-Silv\u0026aacute;n MA, Guittet C, Joukoff S, Bertholet-Thomas A. Lived experiences of patients with distal renal tubular acidosis treated with ADV7103 and of their caregivers: a qualitative study. \u003cem\u003eOrphanet J Rare Dis\u003c/em\u003e. 2022;17(1):141. Published 2022 Mar 28. doi:10.1186/s13023-022-02294-w.\u003c/li\u003e\n\u003cli\u003eAlonso-Varela M, Gil-Pe\u0026ntilde;a H, Coto E, et al. Distal renal tubular acidosis. Clinical manifestations in patients with different underlying gene mutations. \u003cem\u003ePediatr Nephrol\u003c/em\u003e. 2018;33(9):1523-1529. doi:10.1007/s00467-018-3965-8.\u003c/li\u003e\n\u003cli\u003eVerkoelen CF, Verhulst A. Proposed mechanisms in renal tubular crystal retention. \u003cem\u003eKidney Int\u003c/em\u003e. 2007;72(1):13-18. doi:10.1038/sj.ki.5002272.\u003c/li\u003e\n\u003cli\u003eVervaet BA, Verhulst A, De Broe ME, D\u0026apos;Haese PC. The tubular epithelium in the initiation and course of intratubular nephrocalcinosis. \u003cem\u003eUrol Res\u003c/em\u003e. 2010;38(4):249-256. doi:10.1007/s00240-010-0290-5.\u003c/li\u003e\n\u003cli\u003eMumford A, Mumford J, Donald S, et al. The Economic Impact and variability of managing Distal Renal Tubular Acidosis (dRTA) in the UK healthcare setting. (Poster PUK8) Value in Health. 2019;22. doi:10.1016/j.jval.2019.09.2692 \u003c/li\u003e\n\u003cli\u003eDomrongkitchaiporn S, Pongsakul C, Stitchantrakul W, et al. Bone mineral density and histology in distal renal tubular acidosis. \u003cem\u003eKidney Int\u003c/em\u003e. 2001;59(3):1086-1093. doi:10.1046/j.1523-1755.2001.0590031086.x.\u003c/li\u003e\n\u003cli\u003eDomrongkitchaiporn S, Pongskul C, Sirikulchayanonta V, et al. Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. \u003cem\u003eKidney Int\u003c/em\u003e. 2002;62(6):2160-2166. doi:10.1046/j.1523-1755.2002.00656.x.\u003c/li\u003e\n\u003cli\u003eArnett T. Regulation of bone cell function by acid-base balance. \u003cem\u003eProc Nutr Soc\u003c/em\u003e. 2003;62(2):511-520. doi:10.1079/pns2003268.\u003c/li\u003e\n\u003cli\u003eBrandao-Burch A, Utting JC, Orriss IR, Arnett TR. Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization. \u003cem\u003eCalcif Tissue Int\u003c/em\u003e. 2005;77(3):167-174. doi:10.1007/s00223-004-0285-8.\u003c/li\u003e\n\u003cli\u003eMeghji S, Morrison MS, Henderson B, Arnett TR. pH dependence of bone resorption: mouse calvarial osteoclasts are activated by acidosis. \u003cem\u003eAm J Physiol Endocrinol Metab\u003c/em\u003e. 2001;280(1):E112-E119. doi:10.1152/ajpendo.2001.280.1.E112.\u003c/li\u003e\n\u003cli\u003eTaddeo D, Egedy M, Frappier JY. Adherence to treatment in adolescents. \u003cem\u003ePaediatr Child Health\u003c/em\u003e. 2008;13(1):19-24. doi:10.1093/pch/13.1.19.\u003c/li\u003e\n\u003cli\u003eNagra A, McGinnity PM, Davis N, Salmon AP. Implementing transition: Ready Steady Go. \u003cem\u003eArch Dis Child Educ Pract Ed\u003c/em\u003e. 2015;100(6):313-320. doi:10.1136/archdischild-2014-307423.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eMain anthropometric and biological data of Baseline, EoF, Month 48 and EoS of B22CS.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eData in overall population\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB22CS baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB22CS EoF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value: comparison Baseline vs EoF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u0026nbsp;\u003c/strong\u003e(years)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=30\u003c/p\u003e\n \u003cp\u003e10.6\u0026plusmn;6.0\u003c/p\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003cp\u003e9.5\u003c/p\u003e\n \u003cp\u003e2.0-21.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=30\u003c/p\u003e\n \u003cp\u003e16.4\u0026plusmn;6.0\u003c/p\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003cp\u003e7.8-28.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight Z-score\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e-0.6\u0026plusmn;1.0\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e-0.7\u003c/p\u003e\n \u003cp\u003e-3.3-1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e-0.3\u0026plusmn;1.0\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e-0.3\u003c/p\u003e\n \u003cp\u003e-2.2-1.5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep = 0.032\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight Z-score\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=29\u003c/p\u003e\n \u003cp\u003e0.2\u0026plusmn;1.5\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003cp\u003e-2.5-3.2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=29\u003c/p\u003e\n \u003cp\u003e0.6\u0026plusmn;1.3\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e-1.7-3.3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI Z-score\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e0.3\u0026plusmn;1.5\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e-2.3-3.3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e0.2\u0026plusmn;1.4\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e-2.3;2.7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEAS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN patients in normal range (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=26\u003c/p\u003e\n \u003cp\u003e20 (77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=26\u003c/p\u003e\n \u003cp\u003e21 (81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBicarbonatemia\u0026nbsp;\u003c/strong\u003e(mmol/l)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=30\u003c/p\u003e\n \u003cp\u003e22.0\u0026plusmn;3.2\u003c/p\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003cp\u003e22.0\u003c/p\u003e\n \u003cp\u003e13.7-29.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=30\u003c/p\u003e\n \u003cp\u003e22.6\u0026plusmn;2.5\u003c/p\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003cp\u003e22.9\u003c/p\u003e\n \u003cp\u003e17.0-27.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKalemia\u0026nbsp;\u003c/strong\u003e(mmol/l)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=22\u003c/p\u003e\n \u003cp\u003e3.8\u0026plusmn;0.5\u003c/p\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003cp\u003e2.7-4.7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=22\u003c/p\u003e\n \u003cp\u003e3.7\u0026plusmn;0.4\u003c/p\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003cp\u003e3.7\u003c/p\u003e\n \u003cp\u003e2.9-4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFR\u0026nbsp;\u003c/strong\u003e(mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eKDIGO stage, N patients (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eStage 1\u003c/p\u003e\n \u003cp\u003eStage 2\u003c/p\u003e\n \u003cp\u003eStage 3\u003c/p\u003e\n \u003cp\u003eStage 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=23\u003c/p\u003e\n \u003cp\u003e105\u0026plusmn;17\u003c/p\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003cp\u003e100.5\u003c/p\u003e\n \u003cp\u003e79.0-149.8\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20 (87%)\u003c/p\u003e\n \u003cp\u003e3 (13%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=23\u003c/p\u003e\n \u003cp\u003e104\u0026plusmn;20\u003c/p\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003cp\u003e104.5\u003c/p\u003e\n \u003cp\u003e76.5-158.1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (74%)\u003c/p\u003e\n \u003cp\u003e6 (26%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUCa/UCr\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN patients in normal range, (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=27\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=27\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24 (89%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUCi/UCr\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN patients in normal range, (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=20\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=20\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUCa/UCi\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN patients in normal range\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(UCa/UCi \u0026lt;3 mmol/mmol), (%)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=20\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=20\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTmP/GFR\u003c/strong\u003e (mmol/l)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=20\u003c/p\u003e\n \u003cp\u003e1.5\u0026plusmn;0.2\u003c/p\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003cp\u003e1.1-1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=20\u003c/p\u003e\n \u003cp\u003e1.3\u0026plusmn;0.3\u003c/p\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003cp\u003e0.6-1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep = 0.001\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUpH\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eN patients (%)\u003c/p\u003e\n \u003cp\u003e\u0026lt;7.0\u003c/p\u003e\n \u003cp\u003e7.0-8.0\u003c/p\u003e\n \u003cp\u003e\u0026gt;8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=23\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (7.4%)\u003c/p\u003e\n \u003cp\u003e16 (69%)\u003c/p\u003e\n \u003cp\u003e5 (22%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=23\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e16 (69%)\u003c/p\u003e\n \u003cp\u003e7 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCrystalluria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN patients (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eACCP crystal\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN patients (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=17\u003c/p\u003e\n \u003cp\u003e9 (53%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (47%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=17\u003c/p\u003e\n \u003cp\u003e6 (35%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNephrocalcinosis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN patients (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e25 (89%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e26 (93%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNephrolithiasis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN patients (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e6 (21%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=28\u003c/p\u003e\n \u003cp\u003e11 (39%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCalcemia\u003c/strong\u003e (mmol/l)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=26\u003c/p\u003e\n \u003cp\u003e2.38\u0026plusmn;0.10\u003c/p\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003cp\u003e2.2-2.5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=26\u003c/p\u003e\n \u003cp\u003e2.42\u0026plusmn;0.08\u003c/p\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003cp\u003e2.2-2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep = 0.048\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLumbar spine BMD (\u003c/strong\u003eZ-score)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN patients in normal range\u003c/strong\u003e \u003cstrong\u003e(\u0026gt;-2SD) (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=24\u003c/p\u003e\n \u003cp\u003e-1.1\u0026plusmn;1.0\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e-1.1\u003c/p\u003e\n \u003cp\u003e-3.2-0.6\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=24\u003c/p\u003e\n \u003cp\u003e-0.8\u0026plusmn;1.0\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e-0.8\u003c/p\u003e\n \u003cp\u003e-2.7-1.1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep = 0.005\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eData in overall population\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB22CS baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB22CS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMonth 48\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value: Comparison Baseline vs Month 48\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhosphatemia\u0026nbsp;\u003c/strong\u003e(Z-score)\u003cstrong\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=23\u003c/p\u003e\n \u003cp\u003e-0.7\u0026plusmn;0.7\u003c/p\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003cp\u003e-0.7\u003c/p\u003e\n \u003cp\u003e-2.0-1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=23\u003c/p\u003e\n \u003cp\u003e-1.4\u0026plusmn;1.1\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e-1.2\u003c/p\u003e\n \u003cp\u003e-3.5-0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep = 0.005\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ebALPs\u0026nbsp;\u003c/strong\u003e(Z-score)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=9\u003c/p\u003e\n \u003cp\u003e0.9\u0026plusmn;2.2\u003c/p\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003cp\u003e-0.0\u003c/p\u003e\n \u003cp\u003e-1.3-4.9\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=9\u003c/p\u003e\n \u003cp\u003e0.7\u0026plusmn;1.3\u003c/p\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e-0.6-3.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e25-OH-vit-D\u003c/strong\u003e (nmol/L)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=9\u003c/p\u003e\n \u003cp\u003e55.0\u0026plusmn;33.7\u003c/p\u003e\n \u003cp\u003e11.2\u003c/p\u003e\n \u003cp\u003e41.0\u003c/p\u003e\n \u003cp\u003e25.0-127.3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=9\u003c/p\u003e\n \u003cp\u003e51.0\u0026plusmn;19.2\u003c/p\u003e\n \u003cp\u003e6.4\u003c/p\u003e\n \u003cp\u003e52.0\u003c/p\u003e\n \u003cp\u003e33.0-93.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1-25-OH-vit-D\u003c/strong\u003e (pmol/L)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=9\u003c/p\u003e\n \u003cp\u003e164.6\u0026plusmn;54.1\u003c/p\u003e\n \u003cp\u003e18.0\u003c/p\u003e\n \u003cp\u003e172.0\u003c/p\u003e\n \u003cp\u003e100.0-230.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=9\u003c/p\u003e\n \u003cp\u003e158.6\u0026plusmn;36.3\u003c/p\u003e\n \u003cp\u003e12.1\u003c/p\u003e\n \u003cp\u003e159.0\u003c/p\u003e\n \u003cp\u003e111.0-200.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep = NS\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTH\u0026nbsp;\u003c/strong\u003e(ng/L)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN patients in normal range (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=15\u003c/p\u003e\n \u003cp\u003e15.6\u0026plusmn;8.2\u003c/p\u003e\n \u003cp\u003e2.13\u003c/p\u003e\n \u003cp\u003e11.7\u003c/p\u003e\n \u003cp\u003e8.2-37.2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=18\u003c/p\u003e\n \u003cp\u003e16.6\u0026plusmn;6.6\u003c/p\u003e\n \u003cp\u003e1.55\u003c/p\u003e\n \u003cp\u003e16.6\u003c/p\u003e\n \u003cp\u003e7.2-37.8\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eData in overall population\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB22CS baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEoS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.2174%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose\u0026nbsp;\u003c/strong\u003e(mEq/kg/d)\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003eSEM\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eMin-max\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.3483%;\"\u003e\n \u003cp\u003eN=29\u003c/p\u003e\n \u003cp\u003e3.4\u0026plusmn;1.7\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003cp\u003e1.1-8.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2319%;\"\u003e\n \u003cp\u003eN=26\u003c/p\u003e\n \u003cp\u003e2.3\u0026plusmn;1.1\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003cp\u003e1.0-5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0145%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cu\u003e1‑25‑OH‑vit‑D\u003c/u\u003e, 1-25‑dihydroxy‑vitamin D; \u003cu\u003e25‑OH‑vit‑D\u003c/u\u003e, 25‑hydroxy‑vitamin D; \u003cu\u003eACCP\u003c/u\u003e, amorphous carbonated calcium phosphate; \u003cu\u003ebALP\u003c/u\u003e, blood alkaline phosphatase; \u003cu\u003eBMD\u003c/u\u003e: bone mineral density; \u003cu\u003eBMI\u003c/u\u003e, body mass index; \u003cu\u003eEAS\u003c/u\u003e, estimated adult stature; \u003cu\u003eeGFR\u003c/u\u003e, estimated glomerular filtration rate; \u003cu\u003eEoF\u003c/u\u003e, End of Follow‑up; \u003cu\u003eEoS\u003c/u\u003e, End of Study; KDIGO, Kidney Disease: Improving Global Outcomes; \u003cu\u003eMax,\u003c/u\u003e maximum; \u003cu\u003eMin,\u003c/u\u003e minimum; \u003cu\u003eN,\u003c/u\u003e number of patients; \u003cu\u003eNS,\u003c/u\u003e non‑significant; \u003cu\u003ePTH,\u003c/u\u003e parathyroid hormone; \u003cu\u003eSD,\u003c/u\u003e standard deviation; \u003cu\u003eSEM,\u003c/u\u003e standard error of the mean; \u003cu\u003eSoC,\u003c/u\u003e standard of care; \u003cu\u003eTMP/GFR,\u003c/u\u003e ratio of renal tubular reabsorption of phosphorus to glomerular filtration rate; \u003cu\u003eUCa/UCi,\u003c/u\u003e urinary ratio of calcium/citrate; \u003cu\u003eUCa/UCr,\u003c/u\u003e urinary ratio of calcium/creatinine; \u003cu\u003eUCi/UCr,\u003c/u\u003e urinary ratio of citrate/creatinine; UpH, urinary pH.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bone metabolism, Bone Mineral Density, distal Renal Tubular Acidosis, estimated Glomerular Filtration Rate, growth","lastPublishedDoi":"10.21203/rs.3.rs-4957828/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4957828/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDistal renal tubular acidosis (dRTA) is a rare disease characterized by hyperchloremic metabolic acidosis affecting growth, bone and kidney health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe aim of B22CS study was to evaluate long-term safety and efficacy of ADV7103, a prolonged-release alkalizing formulation with twice daily dosing, in children and adults with dRTA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 30 patients with inherited dRTA (mean age:10.6±6.0 years) already treated with ADV7103 entered this long-term study (average of 6 years).\u003c/p\u003e\n\u003cp\u003eADV7103 was well tolerated over the study duration. ADV7103 allowed a sustained control of metabolic acidosis as plasma bicarbonate level was 22.0±3.2 mmol/L at baseline versus 22.6±2.5 mmol/L at the End of Follow-up (EoF), p=NS.\u003c/p\u003e\n\u003cp\u003eFrom baseline to EoF, mean Z-score height significantly increased (-0.6±1.0 to -0.3±1.0, p=0.03), without significant change in weight and body mass index. Kidney function remained stable from baseline to EoF: estimated glomerular filtration rate =105±17 and 104±20 mL/min/1.73m2, respectively, p=NS.\u003c/p\u003e\n\u003cp\u003eUrinary ratios: Calcium/Creatinine (UCa/UCr), Citrate/Creatinine (UCi/UCr), Calcium/Citrate (UCa/UCi) were not significantly different between baseline and EoF (p=NS). Both percentages of patients with nephrocalcinosis and with nephrolithiasis remained stable between baseline and EoF (p=NS).\u003c/p\u003e\n\u003cp\u003eMean lumbar bone mineral density Z-score significantly increased from baseline (-1.1±1.0) to EoF (-0.8±1.0), p=0.005, with significant improvement between baseline and EoF in pre- and post-pubertal patients (p=0.035 and p\u0026lt;0.001, respectively), whilst it was maintained in pubertal patients (p=NS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLong-term data support the good safety and efficacy profile of ADV7103 in the treatment of dRTA with adequate control of metabolic acidosis, stable kidney function and significant positive long-term clinical outcomes.\u003c/p\u003e","manuscriptTitle":"Long-term clinical outcomes with an average of 6 years follow-up in dRTA patients treated with ADV7103 an oral twice-daily fixed and prolonged-release combination of potassium bicarbonate and potassium citrate (Sibnayal®).","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 09:01:38","doi":"10.21203/rs.3.rs-4957828/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-12-07T13:21:06+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-11-15T09:33:16+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-15T05:10:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-30T13:56:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2024-08-29T03:38:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"daa05ff7-01e5-448d-831f-218d958a2712","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-18T16:06:09+00:00","versionOfRecord":{"articleIdentity":"rs-4957828","link":"https://doi.org/10.1186/s13023-025-03953-4","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-08-13 15:58:02","publishedOnDateReadable":"August 13th, 2025"},"versionCreatedAt":"2024-12-18 09:01:38","video":"","vorDoi":"10.1186/s13023-025-03953-4","vorDoiUrl":"https://doi.org/10.1186/s13023-025-03953-4","workflowStages":[]},"version":"v1","identity":"rs-4957828","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4957828","identity":"rs-4957828","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}