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Principal Investigator: Aarti Mathur
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $820,224
Funding agency: National Institute on Aging
PROJECT SUMMARY
Of the 400,000 older (age ≥55) adults living with end-stage renal disease (ESRD), 87% are cognitively
impaired and 25% are subsequently diagnosed with dementia. Incident dementia in older ESRD patients is
associated with a 1.5-fold higher risk of disability and 2-fold higher risk of hospitalization and mortality. Thus,
identifying modifiable risk factors for cognitive decline is critical to the field of geriatric nephrology. A highly
likely risk factor for cognitive decline and incident dementia is secondary hyperparathyroidism (SHPT), which
affects nearly all ESRD patients. SHPT, characterized by high serum parathyroid hormone (PTH), is due to
mineral abnormalities in ESRD. While PTH has been associated with cognitive impairment in non-ESRD
populations we have found that median PTH levels are 54% higher in ESRD patients with cognitive impairment
(p=0.03) and 2-fold higher in those who develop dementia. Furthermore, our preliminary data suggests that
PTH increases other SHPT biomarkers, alkaline phosphatase (ALP, r=0.25, p<0.001) and FGF-23 (r=0.27,
p=0.01), which also correlates with worse executive function (r=0.64, p=0.01). We hypothesize that PTH likely
causes domain-specific cognitive decline both directly by binding to receptors in the brain and indirectly via
release of other biomarkers. Yet, we found a paucity of high-quality studies of PTH, novel bio-markers, and
cognition among ESRD patients in our systematic review; none evaluated cognitive trajectories. SHPT is
modifiable with treatment including poly-pharmacotherapy, surgical parathyroidectomy (PTDx), or waiting until
kidney transplant (KT) to reverse the etiology of SHPT. However, current SHPT treatment guidelines are
inconsistent and ignore cognitive sequelae mainly due to the paucity of high-quality studies characterizing the
impact of SHPT on cognitive function. Understanding the impact of SHPT on cognitive trajectories will allow for
tailored treatment to mitigate cognitive decline, associated morbidity, and improve shared treatment decision-
making among patients and treating surgeons, geriatricians, and nephrologists. Therefore, our central
hypothesis is that SHPT contributes to cognitive decline and incident dementia in older ESRD patients
and can be modified with treatment. This proposal will leverage and expand the scope of the oldest existing
NIA-funded longitudinal cohort study of cognition and frailty among KT patients (3,062 SHPT patients) and
prospectively enroll an additional 600 older SHPT patients in an ancillary study, in which, we will perform
assessments of novel SHPT biomarkers and longitudinal, comprehensive assessments with a new
neurocognitive battery to identify specific cognitive domains directly related to SHPT. We aim to: 1) To quantify
the association between PTH and domain-specific cognitive trajectories among older SHPT patients 2) To test
whether SHPT treatments impact cognitive outcomes, and 3) To develop a decision-making tool surrounding
personalized SHPT treatment to mitigate cognitive decline. Novel incorporation of cognitive trajectories and
SHPT biomarkers will transform practice and improve treatment decision-making in older ESRD patients.
Terms: <21+ years old><Accounting><Adult><Adult Human><Affect><After Care><After-Treatment><Aftercare><Age><Alkaline Phosphatase><Amentia><Ancillary Study><Binding><Biological Markers><Blood Serum><Brain><Brain Nervous System><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Causality><Clinical><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Computerized Medical Record><Cross-Product Ratio><Data><Data Collection><Data Set><Decision Making><Decision Trees><Dementia><Diagnosis><Disturbance in cognition><Drug Therapy><ESRD><Elderly><Electronic Medical Record><Eligibility><Eligibility Determination><Encephalon><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Enrollment><Etiology><Fracture><Funding><Heart Vascular><Hospital Admission><Hospitalization><Impaired cognition><Infrastructure><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Literature><Long-term cohort study><Longitudinal cohort study><Longterm cohort study><Measures><Mediating><Methods><Minerals><Modeling><Modification><Molecular Interaction><Morbidity><Morbidity - disease rate><Nephrology><Neurocognitive><Neuropsychologies><Neuropsychology><Odds Ratio><Older Population><Operative Procedures><Operative Surgical Procedures><Outcome><PTH gene><Parathyrin><Parathyroid Hormone><Parathyroidectomy><Patients><Persons><Pharmacotherapy><Physicians><Population><Process><Protocol Screening><Provider><Public Health><Receptor Protein><Relative Odds><Renal Grafting><Renal Transplantation><Renal Transplants><Risk><Risk Factors><Risk Ratio><Sampling><Secondary Hyperparathyroidism><Secondary to><Serum><Surgeon><Surgical><Surgical Interventions><Surgical Procedure><Testing><Transplant Recipients><abstracting><adulthood><advanced age><ages><alkaline phosphomonoesterase><bio-markers><biologic marker><biomarker><bone fracture><causation><circulatory system><clinical decision-making><clinical practice><cognitive dysfunction><cognitive function><cognitive loss><cohort><customized therapy><customized treatment><dementia risk><design><designing><disability risk><disease causation><drug treatment><elderly patient><enroll><executive control><executive function><frailty><geriatric><glycerophosphatase><hazard><high risk><improved><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><kidney tx><malleable risk><modifiable risk><mortality><neuropsychologic><new marker><novel><novel biomarker><novel marker><older groups><older individuals><older patient><older person><parathormone><patient centered><patient oriented><patient specific therapies><patient specific treatment><pilot test><post treatment><prognostication><prospective><receptor><risk factor for dementia><risk for dementia><risk stratification><senior citizen><stratify risk><surgery><systematic review><tailored medical treatment><tailored therapy><tailored treatment><tool><transplant patient><treatment guidelines><unique treatment><usability><web tool><web-based tool>