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Principal Investigator: NAIM M MAALOUF
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $452,882
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY / ABSTRACT
The incidence of calcium phosphate (CaP) stone disease has markedly increased over the last four decades.
CaP stone formers experience high rates of stone recurrence and frequently need repeat stone surgery,
indicating that current prophylactic medical regimen are suboptimal. The most common metabolic abnormalities
identified in CaP stone formers are hypercalciuria, hypocitraturia, and elevated urine pH, all factors that increase
CaP saturation. Alkali therapy (potassium citrate) is well-established to prevent calcium oxalate stones, in part
by raising urine citrate. However, when tested in CaP stone formers at doses targeted at normalizing citrate
excretion, alkali therapy may worsen CaP stones due to a concomitant rise in urine pH. Hydroxycitrate is a
molecule closely related to citrate that has been shown to prevent CaP nucleation in vitro. However, its efficacy
against CaP stone formation in vivo has not been previously studied. Our preliminary studies suggest that: 1)
Hydroxycitrate can exert a powerful inhibitory effect on CaP crystal growth at low concentrations; 2) Oral
hydroxycitrate ingestion is well-tolerated and raises urine OHCit excretion to concentrations that reduce CaP
crystallization in urine; 3) Oral hydroxycitrate administration increases urine citrate without significantly
increasing urine pH. In this proposal, we will therefore test the overall hypothesis that hydroxycitrate can serve
as a treatment to prevent recurrence of CaP stone disease. To test this hypotheses, we will combine three
complementary approaches: 1) In human metabolic studies conducted in CaP stone formers, we will examine
the short-term impact of a. escalating doses of hydroxycitrate and b. comparative effectiveness of hydroxycitrate
vs alkali therapy (potassium citrate) on urinary biochemical and physicochemical parameters, and CaP crystal
growth and dissolution using atomic force microscopy and bulk crystallization studies conducted on participants’
urine specimen. 2) In an animal model of CaP precipitation, we will assess the long-term impact of the same
interventions to be tested in humans with measurement of urine chemistry, crystalluria, and development of
calcification in kidneys. 3) In vitro, we will manipulate hydroxycitrate, calcium, citrate, and pH, and assess CaP
crystal growth and solubility by a unique combination of techniques spanning multiple length scales. Notably, we
will examine microscopic surface growth by atomic force microscopy, macroscopic crystal nucleation and growth
in a microfluidic device, and the kinetics of bulk crystallization over a range of clinically relevant hydroxycitrate
concentrations. We will test the mechanisms by which hydroxycitrate exerts its impact on CaP crystal growth
and dissolution, and assess the cooperative effects of hydroxycitrate and citrate concentration using a range of
clinically relevant pH and ionic strengths. Overall, based on our strong preliminary data, our innovative but
rigorous techniques, and our cross-disciplinary complimentary studies, we hope that this proposal will help
identify optimal therapeutics for the increasingly encountered and difficult to treat CaP stones.
Terms: <Abnormal Assessment of Metabolism><Address><Alkalies><Animal Model><Animal Models and Related Studies><Atomic Force Microscopy><Biochemical><Biochemistry><Biological Chemistry><Body Weight decreased><Calcified><Calcium><Calcium Oxalate><Caring><Chemicals><Chemistry><Citrates><Clinical><Clinical Trials><Common Rat Strains><Crystal Deposition><Crystal Formation><Crystallization><Data><Deposit><Deposition><Development><Disease><Disorder><Dose><Environment><Excretory function><Force Microscopy><Foundations><Future><Generalized Growth><Growth><Human><In Vitro><Incidence><Ingestion><Intervention><Intervention Strategies><Ionic Strengths><Kidney><Kidney Calculi><Kidney Stones><Kidney Urinary System><Kinetics><Length><Longitudinal Studies><Measurement><Medical><Metabolic><Metabolic Studies><Metabolism Studies><Methods><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Microscopic><Modeling><Modern Man><Molecular><Nephrolithiasis><Operative Procedures><Operative Surgical Procedures><Oral><Outcome><Participant><Prevalence><Preventative therapy><Prevention><Preventive therapy><Prophylactic treatment><Prophylaxis><Rat><Rats Mammals><Rattus><Recurrence><Recurrent><Regimen><Renal Calculi><Renal Stone><Renal Tissue><Renal lithiasis><Reoperation><Repeat Surgery><Research><Research Specimen><Resolution><Risk><Risk Reduction><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Scanning Force Microscopy><Solubility><Specimen><Surface><Surgical><Surgical Interventions><Surgical Procedure><System><Techniques><Testing><Therapeutic><Tissue Growth><Treatment Efficacy><Urinary Calculi><Urinary Stones><Urinary Tract Stones><Urine><Urolith><Weight Loss><Weight Loss Agents><Weight Reduction><Weight-Loss Drugs><body weight loss><calcification><calcium phosphate><calcium phosphate precipitation><calcium salt Ethanedioic acid><clinical relevance><clinically relevant><comparative effectiveness><developmental><excretion><experience><experiment><experimental research><experimental study><experiments><hypercalcinuria><hypercalciuria><hypercalciuric><in vivo><ingest><inhibitor><innovate><innovation><innovative><interstitial><intervention efficacy><interventional strategy><long-term study><longitudinal outcome studies><longterm study><metabolic abnormality assessment><microfluidic chip><model of animal><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><potassium citrate><prevent><preventing><prophylactic><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><renal><resolutions><risk-reducing><social role><spatiotemporal><surgery><therapeutic efficacy><therapy efficacy><thiazide><urinary><urolithiasis><wt-loss>