Sulfate handling in proximal renal tubular defects

Sulfate handling in proximal renal tubular defects | 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 Sulfate handling in proximal renal tubular defects Emil den Bakker, Miriam Wamelink, Desiree E C Smith, Elena N Levtchenko, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8907668/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Renal tubular disease causes loss of electrolytes and other molecules. One of these electrolytes is sulfate, which is reabsorbed by dedicated transporters (NaS1, encoded by SLC13A1 gene). Still, sulfate is rarely measured in clinical practice, although it is essential for development and functioning of several organ systems. The importance of adequate sulfate stores is emphasized by genetic disorders impairing sulfate metabolism in brain, bone and the endocrine system, causing severe neurodevelopmental disorders, skeletal dysplasia and hormonal imbalance. Low availability due to renal loss of sulfate has also been linked to these disorders. Objective To assess the prevalence of renal sulfate wasting in renal tubular diseases. Methods Sulfate was measured in serum and urine of patients with proximal renal tubular disorders using remnant material obtained during routine check-ups. Fractional excretion of sulfate was calculated alongside plasma sulfate concentrations and cystatin C-based eGFR. Results 14 patients were included in whom 1 to 4 paired measurements of urine and plasma sulfate were available. Five patients had decreased plasma sulfate on at least one occasion; 13 patients had increased fractional excretion in at least one measurement. In patients with cystinosis, during cysteamine treatment plasma sulfate levels were often normal despite increased fractional excretion Conclusion Increased sulfate loss is prevalent in children with proximal tubular defects and sulfate stores can be repleted by oral supplements like cysteamine. Sulfate Dent disease Cystinosis Lowe syndrome Figures Figure 1 Introduction Patients with renal tubular diseases lose electrolytes and other molecules into urine. Sodium, potassium, calcium, magnesium, chloride, bicarbonate and phosphate are regularly measured and supplemented if low. Still, sulfate, the fourth most abundant anion, is rarely measured in clinical practice, possibly due to pre-analytical and analytical challenges impairing measurement on common automated platforms ( 1 ). Physiologically, sulfate is incorporated into various molecules through the process of sulfonation in which 3′-Phosphoadenosine-5′-phosphosulfate (PAPS) is the final sulfate donor. Proteoglycans, cholesterol and cholesterol derivatives such as bile acids and steroid hormones as well as exogenous substances are sulfonated which leads to changes in the structure, solubility and function of these molecules ( 2 ). Genetic variants that impair sulfonation in specific tissues cause neurological developmental disorders ( 3 ), distinct forms of skeletal dysplasia ( 4 ), hypertension ( 5 ) and androgen excess ( 6 ). Low serum levels of sulfate due to genetic defects in renal sulfate handling result in similar phenotypes ( 7 , 8 ). Sulfate is filtered in the glomeruli and reabsorbed in the proximal tubule by sodium-sulfate co-transporter 1 encoded by the SLC13A1 gene ( 7 , 8 ). It is likely that patients with a more generalized proximal tubular defect lose sulfate and have lower sulfate stores similar to patients with specific genetic disorders of renal sulfate wasting ( 7 ). This study aims to identify the prevalence and degree of renal sulfate loss in a cohort of pediatric patients with well-defined proximal renal tubular diseases. Methods This study used cross-sectional and retrospective data of patients with proximal renal tubular disorders. Inclusion criterium was a proximal renal tubular defect evidenced by increased excretion of low-molecular weight proteins, phosphate, potassium, bicarbonate and/or glucose. Patients (and/or their caregivers) were approached for consent to use remnant paired blood and urine samples to measure sulfate. The study was approved by the institutional review board of Amsterdam University Medical Center (number 2025.0531). Inclusions and measurements occurred on a convenience basis between January 2024 and October 2025, meaning that patients with more frequent visits in that time period could have more than one measurement. Additional information, such as primary diagnosis, serum and urine creatinine and serum cystatin C levels, medication, height and weight were taken from the patient charts. We specifically recorded cysteamine medication as this drug contains a thiol moiety and is therefore a potential sulfate supplement. Serum and urine sulfate was measured using a Sciex API5000 liquid chromatography–tandem mass spectrometer using negative electrospray ionization. Serum was deproteinated before measurement using acetonitril. Serum and urine creatinine were measured using an IDMS traceable enzymatic method, serum cystatin C with an IFCC-traceable nephelometric immune-assay. GFR was estimated using the cystatin C-based Full Age Spectrum (FAScys) Eq. (9). Fractional excretion (FE) of sulfate was calculated as (urine sulfate (µmol /l) * serum creatinine (µmol /l)) / (serum sulfate (µmol /l) * urine creatinine (mmol/l) *1000). Normal values for serum sulfate (231–432 µmol/l) and fractional excretion of sulfate (0.17–0.34) were taken from Bowling et al and Cole et al along with internal validation tests on healthy subjects in our laboratory ( 10 , 11 ). Results We included 14 individual patients from whom at least one paired measurement of serum and urine sulfate was available. Results are summarized in Table 1 . Primary diagnoses included cystinosis (n = 7; 17 measurements), Dent disease (n = 4; 5 measurements), Lowe syndrome (n = 2; 2 measurements) and post-chemotherapeutic tubulopathy (n = 1; 2 measurements). In 5 out of 14 patients (36%) at least one sulfate measurement was below the reference range. In 13 out of 14 patients (93%), the fractional excretion of sulfate exceeded the reference range on at least one occasion. Cysteamine was given to all cystinosis patients except for patient C-6, in whom the first measurement (C-6-1) was performed at the time of diagnosis before initiation of cysteamine treatment. On 4 out of 5 occasions, the Dent disease patients had elevated FE sulfate, while serum sulfate was borderline low or decreased in all (Fig. 1 ). Patient D-1 initially presented with a skeletal phenotype described as metaphyseal dysplasia along with rickets, which only partially responded to phosphate supplementation. His height still is below his target height range. Table 1 Descriptive results from our cohort of renal Fanconi syndrome patients. $ denotes serum sulfate measurements below the lower limit of normal [N = 231–432 µmol/l]. *denotes fractional excretion (FE) exceeding the upper level of normal [N = 17–34%]. n.a., not available Patient Primary diagnosis Age (years) Serum sulfate (umol/l) FE sulfate Cysteamine dose (mg/m2/day) eGFR cystatin C (ml/min/1.73m 2 ) C-1-1 Cystinosis 5.25 250 0.28 1250 101 C-1-2 Cystinosis 5.42 228 $ 0.24 1184 n.a. C-1-3 Cystinosis 5.67 198 $ 0.32 1184 96 C-1-4 Cystinosis 6.25 251 0.58* 1363 96 C-2-1 Cystinosis 2 242 0.62* 803 n.a. C-3-1 Cystinosis 18.6 393 0.91* 1087 n.a. C-4-1 Cystinosis 12.6 268 0.51* 588 102 C-4-2 Cystinosis 13.3 239 0.29 665 96 C-4-3 Cystinosis 13.6 201 $ 0.53* 779 113 C-5-1 Cystinosis 7.9 296 0.60* 1050 90 C-5-2 Cystinosis 8.3 308 0.64* 1200 76 C-5-3 Cystinosis 8.9 351 0.42* 1350 76 C-6-1 Cystinosis 1.7 205 $ 0.42* 0 52 C-6-2 Cystinosis 1.8 368 0.49* 1429 48 C-6-3 Cystinosis 2.2 443 0.46* 1333 50 C-7-1 Cystinosis 3.5 232 0.48* 1406 111 C-7-2 Cystinosis 3.8 295 0.46* 1384 101 D-1-1 Dent 8.4 126 $ 0.62* 0 66 D-2-1 Dent 11.25 215 $ 0.38* 0 73 D-3-1 Dent 4.6 266 0.35* 0 78 D-3-2 Dent 5.1 250 0.58* 0 87 D-4-1 Dent 15 269 0.20 0 68 L-1-1 Lowe 12.5 398 0.35* 0 42 L-2-1 Lowe 14.9 397 0.47* 0 44 O-1-1 Post chemo 17.1 418 0.52* 0 68 O-1-2 Post chemo 17.6 398 0.38* 0 74 Discussion We show that low serum sulfate and high FE of sulfate are prevalent in pediatric patients with renal Fanconi syndrome. This is in line with a previous report suggesting lower stores of sulfate in these patients ( 12 ). Still, the primary reference cited in this paper was only published in abstract form. While low sulfate levels were most pronounced in patients with Dent disease, most cystinosis patients showed normal serum levels of sulfate despite a high fractional excretion. We suspect that this is due to the high sulfate content of cysteamine, i.e. 13 mmol per gram. Of note, cystinosis patient C-6 had a very low sulfate level and a high fractional excretion before starting cysteamine treatment. In line with our hypothesis, serum sulfate concentrations normalized and the fractional excretion increased even more upon cysteamine treatment. Interestingly, patient C-1 had consistently low serum sulfate in the absence of a high FE sulfate on 3 out of 4 occasions. It also appears that serum sulfate concentrations do not seem to be correlated with cysteamine dose suggesting that there is some variation in the effectiveness of sulfate supplementation with cysteamine or with the timing of sample compared to ingestion of cysteamine. It should be borne in mind that about 40% of sulfate intake occurs in its inorganic form, particularly from drinking water, in which the sulfate content is highly variable. The remainder comes from animal proteins rich in methionine and cysteine ( 13 ). Also, there is significant recycling of sulfate-containing compounds involving PAPS to ensure sufficient sulfate availability. Sulfate clearance is directly related to inulin clearance and patients with severely decreased GFR below 30 ml/min/1.73m 2 have increased serum levels of sulfate ( 14 ). Also, there is an inverse relationship between FE sulfate and inulin clearance ( 14 ). This fits with our observation that the two patients with Lowe syndrome, who have the lowest eGFR in our cohort have the highest serum levels despite having an increased FE sulfate. Due to variance of diagnoses, sulfate supplementation from cysteamine and eGFR in our small cohort we were unable to perform statistical tests to correlate sulfate levels to clinical outcomes that might be related to low sulfate stores such as height, blood pressure, developmental or endocrine disorders. However, patient D-1, who has the lowest serum sulfate level, is growth retarded compared to his target height range and presented with skeletal abnormalities, which persisted after correction of hypophosphatemia. He ultimately required orthopedic surgery. Further research should aim to create a larger, more homogenous cohort of individuals with a proximal tubulopathy to correlate sulfate handling with outcome measures. We suggest starting with a cohort of Dent disease patients as they have the fewest features of extra-renal disease, higher eGFR and do not receive cysteamine as a potential sulfate supplement. Considering the normalization of serum concentrations with cysteamine, further studies should investigate if this can also be achieved with less costly and less toxic over-the-counter drugs like acetylcysteine. Conclusion Sulfate loss is prevalent in pediatric patients with renal Fanconi syndrome and can lead to low serum sulfate concentrations. This can in part be restored with the sulfur containing drug cysteamine, which forms the mainstay of cystinosis therapy. The clinical relevance of these findings requires further study. Declarations We declare no conflicts of interest References den Bakker E, Smith DEC, Finken MJJ, Wamelink MMC, Salomons GS, van de Kamp JM et al (2024) Sulfate: a neglected (but potentially highly relevant) anion. Essays Biochem 68(4):391–399 Langford R, Hurrion E, Dawson PA (2017) Genetics and pathophysiology of mammalian sulfate biology. J Genet Genomics 44(1):7–20 Mencio CP, Hussein RK, Yu P, Geller HM (2021) The Role of Chondroitin Sulfate Proteoglycans in Nervous System Development. J Histochem Cytochem 69(1):61–80 Paganini C, Gramegna Tota C, Superti-Furga A, Rossi A (2020) Skeletal Dysplasias Caused by Sulfation Defects. Int J Mol Sci. ;21(8) Oppelaar JJ, Ferwerda B, Romman MA, Sahebdin GN, Zwinderman AH, Galenkamp H et al (2024) Genetic Variance in Heparan Sulfation Is Associated With Salt Sensitivity. Hypertension 81(10):2101–2112 Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N et al (2009) Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 360(22):2310–2318 van de Kamp JM, Bokenkamp A, Smith DEC, Wamelink MMC, Jansen EEW, Struys EA et al (2023) Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo-epi-metaphyseal dysplasia. Clin Genet 103(1):45–52 Tise CG, Ashton K, de Hayr L, Lee KD, Patkar OL, Krzesinski E et al (2025) Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia. Genet Med Open 3:101958 Pottel H, Delanaye P, Schaeffner E, Dubourg L, Eriksen BO, Melsom T et al (2017) Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. Nephrol Dial Transpl 32(3):497–507 Cole DE, Scriver CR (1980) Age-dependent serum sulfate levels in children and adolescents. Clin Chim Acta 107(1–2):135–139 Bowling FG, Heussler HS, McWhinney A, Dawson PA (2013) Plasma and urinary sulfate determination in a cohort with autism. Biochem Genet 51(1–2):147–153 Cole DE, Evrovski J (1997) Quantitation of sulfate and thiosulfate in clinical samples by ion chromatography. J Chromatogr A 789(1–2):221–232 Morris ME, Murer H (2001) Molecular mechanisms in renal and intestinal sulfate (re)absorption. J Membr Biol 181(1):1–9 Michalk D, Manz F, Muller-Wiefel DE, Scharer K (1982) Renal handling of inorganic sulfate in children with chronic kidney disorders. Min Electrolyte Metab 8(5):255–260 Supplementary Files Graphicalabstrac.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major Revisions Needed 09 Mar, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers invited by journal 20 Feb, 2026 Editor assigned by journal 18 Feb, 2026 First submitted to journal 17 Feb, 2026 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. 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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-8907668","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":594559716,"identity":"2721c142-2bbd-4126-b2f9-ac1d3fb59640","order_by":0,"name":"Emil den Bakker","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYFACxsYDDGwMDAYMbMxAng1UtACvlgZkLWlQUQP89iBrOUxYC7/YYaAtZTZ55uzHkg0+7jmfuOHa4QfMBXi0SM5OBGo5l1Zs2ZN2OHHGs9uJG26nGTDPwKPF4DZQC2Pb4cQNB9KbD/McuG1scDuHgZkHjxZ7iJb/iRvOP28+/OfAOcJaDKTBWg4kbriRdjiZ4cABOYJaJEC2JJxLTtw541myYc+BZDlJoF8O49PCPzv94YMPZXaJ2/nTjCV+HLDj4bud/PAxTwVuLWCQgC5wgICGUTAKRsEoGAUEAAAaSVgbbCkzpwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7300-9378","institution":"Emma Childrens Hospital AMC: Emma Kinderziekenhuis Amsterdam UMC","correspondingAuthor":true,"prefix":"","firstName":"Emil","middleName":"den","lastName":"Bakker","suffix":""},{"id":594559717,"identity":"bf133bc5-71e3-46bb-98ef-ba25d52ef16e","order_by":1,"name":"Miriam Wamelink","email":"","orcid":"","institution":"Amsterdam UMC - Locatie AMC: Amsterdam UMC Locatie AMC","correspondingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"","lastName":"Wamelink","suffix":""},{"id":594559718,"identity":"58d6b147-72a2-48b1-a4cd-99ba830fe820","order_by":2,"name":"Desiree E C Smith","email":"","orcid":"","institution":"Amsterdam UMC - Locatie AMC: Amsterdam UMC Locatie AMC","correspondingAuthor":false,"prefix":"","firstName":"Desiree","middleName":"E C","lastName":"Smith","suffix":""},{"id":594559719,"identity":"ab27abb0-387e-434c-a06b-9f7a24732958","order_by":3,"name":"Elena N Levtchenko","email":"","orcid":"","institution":"Emma Childrens Hospital AMC: Emma Kinderziekenhuis Amsterdam UMC","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"N","lastName":"Levtchenko","suffix":""},{"id":594559720,"identity":"7f4a91a3-07b7-4de9-beb7-a16f5979181f","order_by":4,"name":"Arend Bökenkamp","email":"","orcid":"","institution":"Emma Childrens Hospital AMC: Emma Kinderziekenhuis Amsterdam UMC","correspondingAuthor":false,"prefix":"","firstName":"Arend","middleName":"","lastName":"Bökenkamp","suffix":""}],"badges":[],"createdAt":"2026-02-18 09:17:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8907668/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8907668/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103565959,"identity":"38b639ff-25da-4c13-9ac7-338ed590dba4","added_by":"auto","created_at":"2026-02-27 07:20:54","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31533,"visible":true,"origin":"","legend":"\u003cp\u003eserum sulfate concentration and FE sulfate grouped by diagnosis. eGFR: estimated glomerular filtration rate, FE: fractional excretion, LLN: lower level of normal, ULN: upper level of normal\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8907668/v1/be918a2bb88415a6728cad77.jpg"},{"id":104398155,"identity":"730a9d67-4efc-424c-8666-e72a8d90c0dc","added_by":"auto","created_at":"2026-03-11 11:59:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":511570,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8907668/v1/7f296f69-4d48-429d-8d6b-448049aaf4eb.pdf"},{"id":103565960,"identity":"5de716f0-46e2-41ff-8748-17343edbc1a2","added_by":"auto","created_at":"2026-02-27 07:20:54","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":308596,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstrac.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8907668/v1/4f8634dd49bf07ef6556322a.pdf"}],"financialInterests":"","formattedTitle":"Sulfate handling in proximal renal tubular defects","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePatients with renal tubular diseases lose electrolytes and other molecules into urine. Sodium, potassium, calcium, magnesium, chloride, bicarbonate and phosphate are regularly measured and supplemented if low. Still, sulfate, the fourth most abundant anion, is rarely measured in clinical practice, possibly due to pre-analytical and analytical challenges impairing measurement on common automated platforms (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePhysiologically, sulfate is incorporated into various molecules through the process of sulfonation in which 3\u0026prime;-Phosphoadenosine-5\u0026prime;-phosphosulfate (PAPS) is the final sulfate donor. Proteoglycans, cholesterol and cholesterol derivatives such as bile acids and steroid hormones as well as exogenous substances are sulfonated which leads to changes in the structure, solubility and function of these molecules (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Genetic variants that impair sulfonation in specific tissues cause neurological developmental disorders (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), distinct forms of skeletal dysplasia (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), hypertension (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and androgen excess (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Low serum levels of sulfate due to genetic defects in renal sulfate handling result in similar phenotypes (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSulfate is filtered in the glomeruli and reabsorbed in the proximal tubule by sodium-sulfate co-transporter 1 encoded by the \u003cem\u003eSLC13A1\u003c/em\u003e gene (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). It is likely that patients with a more generalized proximal tubular defect lose sulfate and have lower sulfate stores similar to patients with specific genetic disorders of renal sulfate wasting (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study aims to identify the prevalence and degree of renal sulfate loss in a cohort of pediatric patients with well-defined proximal renal tubular diseases.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis study used cross-sectional and retrospective data of patients with proximal renal tubular disorders. Inclusion criterium was a proximal renal tubular defect evidenced by increased excretion of low-molecular weight proteins, phosphate, potassium, bicarbonate and/or glucose. Patients (and/or their caregivers) were approached for consent to use remnant paired blood and urine samples to measure sulfate. The study was approved by the institutional review board of Amsterdam University Medical Center (number 2025.0531). Inclusions and measurements occurred on a convenience basis between January 2024 and October 2025, meaning that patients with more frequent visits in that time period could have more than one measurement. Additional information, such as primary diagnosis, serum and urine creatinine and serum cystatin C levels, medication, height and weight were taken from the patient charts. We specifically recorded cysteamine medication as this drug contains a thiol moiety and is therefore a potential sulfate supplement.\u003c/p\u003e \u003cp\u003eSerum and urine sulfate was measured using a Sciex API5000 liquid chromatography\u0026ndash;tandem mass spectrometer using negative electrospray ionization. Serum was deproteinated before measurement using acetonitril.\u003c/p\u003e \u003cp\u003eSerum and urine creatinine were measured using an IDMS traceable enzymatic method, serum cystatin C with an IFCC-traceable nephelometric immune-assay.\u003c/p\u003e \u003cp\u003eGFR was estimated using the cystatin C-based Full Age Spectrum (FAScys) Eq.\u0026nbsp;(9). Fractional excretion (FE) of sulfate was calculated as (urine sulfate (\u0026micro;mol /l) * serum creatinine (\u0026micro;mol /l)) / (serum sulfate (\u0026micro;mol /l) * urine creatinine (mmol/l) *1000). Normal values for serum sulfate (231\u0026ndash;432 \u0026micro;mol/l) and fractional excretion of sulfate (0.17\u0026ndash;0.34) were taken from Bowling et al and Cole et al along with internal validation tests on healthy subjects in our laboratory (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe included 14 individual patients from whom at least one paired measurement of serum and urine sulfate was available. Results are summarized in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Primary diagnoses included cystinosis (n\u0026thinsp;=\u0026thinsp;7; 17 measurements), Dent disease (n\u0026thinsp;=\u0026thinsp;4; 5 measurements), Lowe syndrome (n\u0026thinsp;=\u0026thinsp;2; 2 measurements) and post-chemotherapeutic tubulopathy (n\u0026thinsp;=\u0026thinsp;1; 2 measurements). In 5 out of 14 patients (36%) at least one sulfate measurement was below the reference range. In 13 out of 14 patients (93%), the fractional excretion of sulfate exceeded the reference range on at least one occasion. Cysteamine was given to all cystinosis patients except for patient C-6, in whom the first measurement (C-6-1) was performed at the time of diagnosis before initiation of cysteamine treatment. On 4 out of 5 occasions, the Dent disease patients had elevated FE sulfate, while serum sulfate was borderline low or decreased in all (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patient D-1 initially presented with a skeletal phenotype described as metaphyseal dysplasia along with rickets, which only partially responded to phosphate supplementation. His height still is below his target height range.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescriptive results from our cohort of renal Fanconi syndrome patients. \u003csup\u003e$\u003c/sup\u003edenotes serum sulfate measurements below the lower limit of normal [N\u0026thinsp;=\u0026thinsp;231\u0026ndash;432 \u0026micro;mol/l]. *denotes fractional excretion (FE) exceeding the upper level of normal [N\u0026thinsp;=\u0026thinsp;17\u0026ndash;34%]. n.a., not available\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrimary diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum sulfate (umol/l)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFE sulfate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCysteamine dose (mg/m2/day)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eeGFR cystatin C\u003c/p\u003e \u003cp\u003e(ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-1-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-1-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e228\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-1-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e198\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-1-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e251\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-2-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e803\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-3-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e393\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.91*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-4-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e268\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.51*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-4-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e239\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-4-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e201\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.53*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e779\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-5-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.60*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-5-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e308\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.64*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-5-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e351\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.42*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-6-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e205\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.42*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-6-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.49*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-6-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e443\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.46*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-7-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.48*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-7-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystinosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.46*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1384\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-1-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e126\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-2-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e215\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.38*\u003c/p\u003e \u003c/td\u003e \u003ctd 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align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL-1-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLowe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e398\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.35*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e 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\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.52*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO-1-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost chemo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e398\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.38*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe show that low serum sulfate and high FE of sulfate are prevalent in pediatric patients with renal Fanconi syndrome. This is in line with a previous report suggesting lower stores of sulfate in these patients (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Still, the primary reference cited in this paper was only published in abstract form. While low sulfate levels were most pronounced in patients with Dent disease, most cystinosis patients showed normal serum levels of sulfate despite a high fractional excretion. We suspect that this is due to the high sulfate content of cysteamine, i.e. 13 mmol per gram. Of note, cystinosis patient C-6 had a very low sulfate level and a high fractional excretion before starting cysteamine treatment. In line with our hypothesis, serum sulfate concentrations normalized and the fractional excretion increased even more upon cysteamine treatment. Interestingly, patient C-1 had consistently low serum sulfate in the absence of a high FE sulfate on 3 out of 4 occasions. It also appears that serum sulfate concentrations do not seem to be correlated with cysteamine dose suggesting that there is some variation in the effectiveness of sulfate supplementation with cysteamine or with the timing of sample compared to ingestion of cysteamine. It should be borne in mind that about 40% of sulfate intake occurs in its inorganic form, particularly from drinking water, in which the sulfate content is highly variable. The remainder comes from animal proteins rich in methionine and cysteine (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Also, there is significant recycling of sulfate-containing compounds involving PAPS to ensure sufficient sulfate availability.\u003c/p\u003e \u003cp\u003eSulfate clearance is directly related to inulin clearance and patients with severely decreased GFR below 30 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e have increased serum levels of sulfate (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Also, there is an inverse relationship between FE sulfate and inulin clearance (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). This fits with our observation that the two patients with Lowe syndrome, who have the lowest eGFR in our cohort have the highest serum levels despite having an increased FE sulfate.\u003c/p\u003e \u003cp\u003eDue to variance of diagnoses, sulfate supplementation from cysteamine and eGFR in our small cohort we were unable to perform statistical tests to correlate sulfate levels to clinical outcomes that might be related to low sulfate stores such as height, blood pressure, developmental or endocrine disorders. However, patient D-1, who has the lowest serum sulfate level, is growth retarded compared to his target height range and presented with skeletal abnormalities, which persisted after correction of hypophosphatemia. He ultimately required orthopedic surgery.\u003c/p\u003e \u003cp\u003eFurther research should aim to create a larger, more homogenous cohort of individuals with a proximal tubulopathy to correlate sulfate handling with outcome measures. We suggest starting with a cohort of Dent disease patients as they have the fewest features of extra-renal disease, higher eGFR and do not receive cysteamine as a potential sulfate supplement. Considering the normalization of serum concentrations with cysteamine, further studies should investigate if this can also be achieved with less costly and less toxic over-the-counter drugs like acetylcysteine.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSulfate loss is prevalent in pediatric patients with renal Fanconi syndrome and can lead to low serum sulfate concentrations. This can in part be restored with the sulfur containing drug cysteamine, which forms the mainstay of cystinosis therapy. The clinical relevance of these findings requires further study.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eWe declare no conflicts of interest\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eden Bakker E, Smith DEC, Finken MJJ, Wamelink MMC, Salomons GS, van de Kamp JM et al (2024) Sulfate: a neglected (but potentially highly relevant) anion. Essays Biochem 68(4):391\u0026ndash;399\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLangford R, Hurrion E, Dawson PA (2017) Genetics and pathophysiology of mammalian sulfate biology. J Genet Genomics 44(1):7\u0026ndash;20\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMencio CP, Hussein RK, Yu P, Geller HM (2021) The Role of Chondroitin Sulfate Proteoglycans in Nervous System Development. J Histochem Cytochem 69(1):61\u0026ndash;80\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaganini C, Gramegna Tota C, Superti-Furga A, Rossi A (2020) Skeletal Dysplasias Caused by Sulfation Defects. Int J Mol Sci. ;21(8)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOppelaar JJ, Ferwerda B, Romman MA, Sahebdin GN, Zwinderman AH, Galenkamp H et al (2024) Genetic Variance in Heparan Sulfation Is Associated With Salt Sensitivity. Hypertension 81(10):2101\u0026ndash;2112\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N et al (2009) Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 360(22):2310\u0026ndash;2318\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan de Kamp JM, Bokenkamp A, Smith DEC, Wamelink MMC, Jansen EEW, Struys EA et al (2023) Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo-epi-metaphyseal dysplasia. Clin Genet 103(1):45\u0026ndash;52\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTise CG, Ashton K, de Hayr L, Lee KD, Patkar OL, Krzesinski E et al (2025) Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia. Genet Med Open 3:101958\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePottel H, Delanaye P, Schaeffner E, Dubourg L, Eriksen BO, Melsom T et al (2017) Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. Nephrol Dial Transpl 32(3):497\u0026ndash;507\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCole DE, Scriver CR (1980) Age-dependent serum sulfate levels in children and adolescents. Clin Chim Acta 107(1\u0026ndash;2):135\u0026ndash;139\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBowling FG, Heussler HS, McWhinney A, Dawson PA (2013) Plasma and urinary sulfate determination in a cohort with autism. Biochem Genet 51(1\u0026ndash;2):147\u0026ndash;153\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCole DE, Evrovski J (1997) Quantitation of sulfate and thiosulfate in clinical samples by ion chromatography. J Chromatogr A 789(1\u0026ndash;2):221\u0026ndash;232\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorris ME, Murer H (2001) Molecular mechanisms in renal and intestinal sulfate (re)absorption. J Membr Biol 181(1):1\u0026ndash;9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMichalk D, Manz F, Muller-Wiefel DE, Scharer K (1982) Renal handling of inorganic sulfate in children with chronic kidney disorders. Min Electrolyte Metab 8(5):255\u0026ndash;260\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Sulfate, Dent disease, Cystinosis, Lowe syndrome","lastPublishedDoi":"10.21203/rs.3.rs-8907668/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8907668/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRenal tubular disease causes loss of electrolytes and other molecules. One of these electrolytes is sulfate, which is reabsorbed by dedicated transporters (NaS1, encoded by \u003cem\u003eSLC13A1\u003c/em\u003e gene). Still, sulfate is rarely measured in clinical practice, although it is essential for development and functioning of several organ systems. The importance of adequate sulfate stores is emphasized by genetic disorders impairing sulfate metabolism in brain, bone and the endocrine system, causing severe neurodevelopmental disorders, skeletal dysplasia and hormonal imbalance. Low availability due to renal loss of sulfate has also been linked to these disorders.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo assess the prevalence of renal sulfate wasting in renal tubular diseases.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e Sulfate was measured in serum and urine of patients with proximal renal tubular disorders using remnant material obtained during routine check-ups. Fractional excretion of sulfate was calculated alongside plasma sulfate concentrations and cystatin C-based eGFR.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e14 patients were included in whom 1 to 4 paired measurements of urine and plasma sulfate were available. Five patients had decreased plasma sulfate on at least one occasion; 13 patients had increased fractional excretion in at least one measurement. In patients with cystinosis, during cysteamine treatment plasma sulfate levels were often normal despite increased fractional excretion\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIncreased sulfate loss is prevalent in children with proximal tubular defects and sulfate stores can be repleted by oral supplements like cysteamine.\u003c/p\u003e","manuscriptTitle":"Sulfate handling in proximal renal tubular defects","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 07:20:48","doi":"10.21203/rs.3.rs-8907668/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2026-03-09T13:01:59+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-02-20T18:19:22+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-20T16:12:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-18T15:34:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2026-02-18T04:16:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e11c2b28-24d2-4621-a6b8-4a2e1c8ef025","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-07T06:01:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-27 07:20:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8907668","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8907668","identity":"rs-8907668","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}