DeCure for Nephrolithiasis/osteoporosis, hypophosphatemic
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for nephrolithiasis/osteoporosis, hypophosphatemic — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNephrolithiasis/osteoporosis, hypophosphatemic maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for nephrolithiasis/osteoporosis, hypophosphatemic is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
In a four-generation family with apparent dominant hypophosphatemic rickets with hypercalciuria, whole exome analysis identified digenic heterozygous mutations in SLC34A1 and SLC34A3. The proband and her affected sister and mother carried pathogenic mutations in both genes; the brother, father, and paternal grandmother carried only the SLC34A3 mutation and were clinically less affected. Renal phosphate-wasting showed both a gene dosage-effect and age-dependent attenuation of severity. A separate case report describes a 38-year-old Chinese woman with hypophosphatemic kidney stones and osteoporosis who carried a novel heterozygous SLC34A1 mutation (c.1753T>C, p.S585P) inherited from her mother, which the authors believe is the cause of pathology.
A longitudinal retrospective study of 12,794 free-living Caucasian subjects from southern Italy found that osteoporosis is a predictive factor for incident nephrolithiasis. Over a mean follow-up of 19.5 months, 516 subjects had an incident kidney stone episode. Subjects with osteoporosis had a hazard ratio of 1.33 (95% CI 1.01–1.74, p = 0.04) for nephrolithiasis compared to those without osteoporosis. The study excluded subjects under 40 or with signs of secondary osteoporosis.
In a retrospective cohort of 611 primary hyperparathyroidism patients, 13.9% had nephrolithiasis, but only 4.7% of asymptomatic patients screened for stones had calculi identified, a rate not very dissimilar to the non-PHPT population. Younger age (p < 0.001) and male gender (p = 0.003) were the only independent predictors of nephrolithiasis. Osteoporosis was present in 48.4% of patients with DXA data (223/461); older age (p < 0.001), lower BMI (p = 0.002), and lower creatinine (p = 0.006) were independently associated with osteoporosis, while calcium and PTH were not independently associated with lower Z-score except for higher PTH at the hip (p = 0.009). Mortality was associated with older age, social deprivation, and higher adjusted calcium (p = 0.009), but not independently with PTH.
What is still missing is prospective data on whether treating osteoporosis reduces nephrolithiasis risk, and whether screening asymptomatic PHPT patients for stones is worthwhile given the low yield. The genetic findings highlight the challenge of assigning causality to digenic or novel heterozygous variants without functional confirmation. No trial has tested whether phosphate supplementation or calcimimetics alter stone or fracture outcomes in these specific hypophosphatemic or hyperparathyroid populations. Patient stratification by genotype and age, and funding for adequately powered randomised trials, remain absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Clinical Endocrinology & Metabolism · 2020 · 30 citations · open access
Digenic Heterozygous Mutations in SLC34A3 and SLC34A1 Cause Dominant Hypophosphatemic Rickets with Hypercalciuria
AbstractCONTEXT: Hypophosphatemia and metabolic bone disease are associated with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to biallelic mutations of SLC34A3 encoding the NPT2C sodium-phosphate cotransporter and nephrolithiasis/osteoporosis, hypophosphatemic 1 (NPHLOP1) due to monoallelic mutations in SLC34A1 encoding the NPT2A sodium-phosphate cotransporter. OBJECTIVE: To identify a genetic cause of apparent dominant transmission of HHRH. DESIGN AND SETTING: Retrospective and prospective analysis of clinical and molecular characteristics of patients studied in 2 academic medical centers. METHODS: We recruited 4 affected and 3 unaffected members of a 4-generation family in which the proband presented with apparent HHRH. We performed clinical examinations, biochemical and radiological analyses, and molecular studies of genomic DNA. RESULTS: The proband and her affected sister and mother carried pathogenic heterozygous mutations in 2 related genes, SLC34A1 (exon 13, c.1535G>A; p.R512H) and SLC34A3 (exon 13, c.1561dupC; L521Pfs*72). The proband and her affected sister inherited both gene mutations from their mother, while their clinically less affected brother, father, and paternal grandmother carried only the SLC34A3 mutation. Renal phosphate-wasting exhibited both a gene dosage-effect and an age-dependent attenuation of severity. CONCLUSIONS: We describe a kindred with autosomal dominant hypophosphatemic rickets in which whole exome analysis identified digenic heterozygous mutations in SLC34A1 and SLC34A3. Subjects with both mutations were more severely affected than subjects carrying only one mutation. These findings highlight the challenges of assigning causality to plausible genetic variants in the next generation sequencing era.
Calcified Tissue International · 2020 · 19 citations · open access
Osteoporosis is a Predictive Factor for Nephrolithiasis in an Adult Free-Living Caucasian Population From Southern Italy: A Longitudinal Retrospective Study Based on a General Practice Database
AbstractOsteoporosis and nephrolithiasis are common multifactorial disorders with high incidence and prevalence in the adult population worldwide. Both are associated with high morbidity and mortality if not correctly diagnosed and accurately treated. Nephrolithiasis is considered a risk factor for reduced bone mineral density. Aim of this retrospective longitudinal study was to evaluate if osteoporosis is a predictive factor for the nephrolithiasis occurrence. Free-living subjects referring to "COMEGEN" general practitioners cooperative operating in Naples, Southern Italy. Twelve thousand seven hundred ninety-four Caucasian subjects (12,165 female) who performed bone mineral density by dual-energy X-ray absorptiometry and have a negative personal history for nephrolithiasis. Subjects aged less than 40 years or with signs or symptoms suggestive of secondary osteoporosis were excluded from the study. In a mean lapse of time of 19.5 months, 516 subjects had an incident episode of nephrolithiasis. Subjects with osteoporosis had an increased risk of nephrolithiasis than subjects without osteoporosis (Hazard Ratio = 1.33, 95% Confidence Interval 1.01-1.74, p = 0.04). Free-living adult subjects over the age of 40 with idiopathic osteoporosis have an increased risk of incident nephrolithiasis, suggesting the advisability of appropriate investigation and treatment of the metabolic alterations predisposing to nephrolithiasis in patients with osteoporosis. The study protocol was approved by the ASL Napoli 1 Ethical Committee, protocol number 0018508/2018.
Journal of International Medical Research · 2020 · 11 citations · open access
Heterozygous mutation of <i>SLC34A1</i> in patients with hypophosphatemic kidney stones and osteoporosis: a case report
AbstractHypophosphatemic kidney stones with osteoporosis is a rare disease clinically. Mutations in the solute carrier family 34 member 1 gene ( SLC34A1), encoding NaPi-IIa, are considered to be associated with this disease. In this report, a 38-year-old Chinese woman was diagnosed with hypophosphatemic kidney stones with osteoporosis. Her clinical features were recorded, and biochemical tests and DNA sequencing were performed of the proband and her parents. Sequencing revealed that she inherited the c.1753T>C SLC34A1 mutation from her mother. This mutation in exon 13 of SLC34A1 causes a substitution of serine with proline (p. S585P) at position 585 of NaPi-IIa. This is a novel mutation that has not previously been reported, and which shows autosomal dominant inheritance. It is expected to lead to changes in protein function, and we believe that it is the cause of pathology in our patient.
Data Archiving and Networked Services (DANS) · 2019 · 0 citations · open access
Data from: Predictors of nephrolithiasis, osteoporosis and mortality in primary hyperparathyroidism
AbstractContext: Primary Hyperparathyroidism (PHPT) has a prevalence of 0.86% and is associated with increased risk of nephrolithiasis and osteoporosis. PHPT may also be associated with an increased risk of cardiovascular disease and mortality. Objective: To identify risk factors for nephrolithiasis, osteoporosis and mortality in PHPT. Design: Retrospective cohort study. Setting: University teaching hospital. Patients: PHPT presenting between 2006 – 2014 (n = 611). Main outcome measures: Assessment of nephrolithiasis, osteoporosis and mortality. Results: 13.9% of PHPT patients had nephrolithiasis. Most had already documented stone disease and only 4.7% of asymptomatic patients screened for renal stones had calculi identified, not very dissimilar to the rate in the non-PHPT population. Younger age (P < 0.001) and male gender (P = 0.003) were the only independent predictors of nephrolithiasis. 48.4% of patients with DXA data had osteoporosis (223/461). Older age (P < 0.001), lower BMI (P = 0.002) and lower creatinine (P = 0.006) were independently associated with a diagnosis of osteoporosis. Higher PTH was independently associated with lower Z-score at the hip (P = 0.009), but otherwise calcium and PTH were not associated with lower Z-score. Mortality in PHPT was associated with older age (P < 0.008), social deprivation (P = 0.028) and adjusted calcium (P = 0.009) but not independently with PTH at diagnosis. Conclusions: Screening for nephrolithiasis has a low yield, particularly in lower risk patients. Osteoporosis is only minimally associated with biochemical indices of PHPT. Mortality is associated with higher calcium (and possibly vitamin D deficiency) but not PTH.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
