Secondary Hyperparathyroidism (CKD-MBD) Treatment and the Risk of Dementia

Aarti Mathur; JiYoon B. Ahn; Whitney Sutton; NadiaM. Chu; Alden L. Gross; Dorry L. Segev; Mara McAdams-DeMarco

Disclosures

Nephrol Dial Transplant. 2022;37(11):2111-2118.

Abstract and Introduction

Abstract

Graphical Abstract

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Background: Elevated parathyroid hormone (PTH) levels have been reported as a potential risk factor for cognitive impairment. Compared with the general population, older adults with end-stage renal disease (ESRD) who are frequently affected by secondary hyperparathyroidism (SHPT) are at increased risk of developing dementia. The main objective of our study was to evaluate if the risk of dementia in older (age ≥66 years) ESRD patients differed if they were treated for SHPT.

Methods: Using the United States Renal Data System and Medicare claims, we identified 189 433 older adults without a diagnosis of dementia, who initiated dialysis between 2006 and 2016. SHPT treatment was defined as the use of vitamin D analogs, phosphate binders, calcimimetics or parathyroidectomy. We quantified the association between treated SHPT and incident dementia during dialysis using a multivariable Cox proportional hazards model with inverse probability weighting, considering SHPT treatment as a time-varying exposure.

Results: Of 189 433 older ESRD adults, 92% had a claims diagnosis code of SHPT and 123 388 (65%) were treated for SHPT. The rate of incident dementia was 6 cases per 100 person-years among SHPT treated patients compared with 11 cases per 100 person-years among untreated patients. Compared with untreated SHPT patients, the risk of dementia was 42% lower [adjusted hazard ratio (aHR) = 0.58, 95% confidence interval (CI): 0.56–0.59] among SHPT treated patients. The magnitude of the beneficial effect of SHPT treatment differed by sex (P _interaction = .02) and race (P _interaction ≤ .01), with females (aHR = 0.56, 95% CI: 0.54–0.58) and those of Asian (aHR = 0.51, 95% CI: 0.46–0.57) or Black race (aHR = 0.51, 95% CI: 0.48–0.53) having a greatest reduction in dementia risk.

Conclusion: Receiving treatment for SHPT was associated with a lower risk of incident dementia among older patients with ESRD. This work provides additional support for the treatment of SHPT in older ESRD patients.

Introduction

Up to 70% of older (age >65 years) patients with end-stage renal disease (ESRD) suffer from cognitive impairment.^[2–4] Furthermore, the incidence of dementia and Alzheimer's disease, the most commonly diagnosed types of dementia, begins to rise soon after dialysis initiation and is 10 times higher than the incidence in community-dwelling older adults.^[5] Older ESRD patients who develop dementia are at a 1.5-fold higher risk of disability, 2-fold increased risk of hospitalization and a 2-fold higher risk of subsequent mortality.^[5] Age, race, sex, diabetes, hemodialysis vintage, prior history of stroke and race have been identified as risk factors for cognitive impairment and dementia among ESRD patients, however, these are difficult to modify.^[6,7] Therefore, the identification of modifiable risk factors for cognitive decline and dementia in older ESRD patients is critical.

Secondary hyperparathyroidism (SHPT), characterized by severely elevated parathyroid hormone levels (PTH), arises from the metabolic abnormalities of ESRD affecting the majority of ESRD patients and represents one such potentially modifiable dementia risk factor. PTH can cross the blood–brain barrier binding to receptors in the brain thereby affecting cognition.^[8–10] In patients without ESRD, elevated PTH levels are associated with impaired cognitive function and dementia.^[11–15]

Further, several single-institution studies have demonstrated improvement in specific cognitive domains after treatment of SHPT;^[16–18] such treatments for SHPT include medications like phosphate binders, vitamin D analogs and calcimimetics or surgical parathyroidectomy. Yet, despite the existence of SHPT treatment guidelines, it remains untreated in up to 30%–60% of patients, representing a potential missed opportunity to address one of the central complications of ESRD: cognitive decline and dementia.^[1,19,20] Furthermore, SHPT disease severity, management and outcomes vary by race.^[21–23]

Given that PTH impacts cognitive function, we hypothesized that the incidence of dementia would differ between older ESRD patients who were and were not treated for SHPT. Therefore, we sought to: (i) investigate whether SHPT treatment was associated with dementia risk and specifically Alzheimer's disease risk; and (ii) identify subgroups of SHPT patients who would benefit the most from SHPT treatment.

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Table 1. Characteristics of older (aged ≥66 years) end-stage renal disease patients by secondary hyperparathyroidism treatment status ( n = 189 433)
	Overall	Patients without SHPT treatment (n = 66 045)	Patients with SHPT treatment (n = 123 388)	P-value
Age at diagnosis (years)				<.001
66–69, n (%)	22.4	18.3	24.5
70–79, n (%)	48.8	46.5	50.1
80 or older, n (%)	28.8	35.2	25.4
Female, n (%)	51.0	48.9	52.1	<.001
Race				<.001
White, n (%)	75.2	77.9	73.7
Black, n (%)	18.8	17.3	19.5
Asian, n (%)	4.4	3.4	5.0
Other, n (%)	1.6	1.3	1.8
Currently employed, n (%)	2.0	1.6	2.3	<.001
Geographic regions				<.001
Northeast, n (%)	18.6	18.1	18.9
South, n (%)	37.4	37.2	37.6
Midwest, n (%)	25.7	27.5	24.7
West, n (%)	18.3	17.2	18.8
BMI (kg/m²)				<.001
<25, n (%)	36.0	38.9	34.5
25–29.9, n (%)	29.8	29.2	30.1
≥30, n (%)	34.2	31.9	35.4
Modality—hemodialysis, n (%)	94.2	95.7	93.4	<.001
Primary cause of ESRD				<.001
Diabetes mellitus, n (%)	43.9	40.1	46.0
Hypertension, n (%)	35.2	35.5	35.0
Glomerulonephritis, n (%)	5.0	4.3	5.3
Others, n (%)	15.9	20.1	13.7
Comorbidity
Hypertension, n (%)	87.6	85.4	88.8	<.001
Diabetes mellitus, n (%)	55.5	53.1	56.7	<.001
Cerebrovascular disease, n (%)	10.9	12.2	10.2	<.001
Atherosclerotic heart disease, n (%)	25.3	26.1	24.8	<.001
Heart failure, n (%)	39.9	43.5	37.9	<.001
Peripheral vascular disease, n (%)	15.6	16.9	15.0	<.001
Cancer, n (%)	10.5	12.0	9.8	<.001
Functional impairment, n (%)	19.6	25.8	16.2	<.001
Alcohol dependence, n (%)	0.7	1.0	0.6	<.001
Current smoker, n (%)	3.8	3.7	3.9	.13

SHPT, secondary hyperparathyroidism; BMI, body mass index; ESRD, end-stage renal disease.

Table 2. Risk of incident dementia in older ESRD patients with secondary hyperparathyroidism (SHPT) comparing those who received treatment during dialysis in our study cohort (A) or only in patients with a diagnosis code of SHPT (B) with those who did not receive treatment, and also comparing treatment by parathyroidectomy compared with cinacalcet (C). Adjusted hazard ratio (aHR) and 95% confidence interval (CI) is reported
SHPT treatment	Incident rate (cases/100 person-years)	Risk of incident dementia [aHR (95% CI)] ^a
A. Entire cohort
No	11	Reference
Yes	6	0.58 (0.56–0.59)
B. Restricted only to patients with claims diagnosis of SHPT
No	10	Reference
Yes	6	0.63 (0.62–0.65)
C. Restricted only to patients receiving either treatment
Cinacalcet	7.3	Reference
Parathyroidectomy	6.2	0.91 (0.66–1.26)

^aAdjusted for age at diagnosis sex, race/ethnicity, employment, geographic region, body mass index, dialysis modality type, primary cause of end-stage renal disease, comorbidities (hypertension, diabetes mellitus, cerebrovascular disease, atherosclerotic heart disease, heart failure, peripheral vascular disease, cancer, functional impairment, alcohol dependence and smoking) and days of previous medication prescription.

Table 3. The impact of secondary hyperparathyroidism treatment on incident dementia stratified by age, sex, race and diabetes status compared with no treatment. Hazard ratios were adjusted for age at diagnosis, sex, race/ethnicity, employment, geographic region, body mass index, dialysis modality type, primary cause of end-stage renal disease, comorbidities (hypertension, diabetes mellitus, cerebrovascular disease, atherosclerotic heart disease, heart failure, peripheral vascular disease, cancer, functional impairment, alcohol dependence and smoking) and days of previous medication prescriptions
Effect modifier	Incident dementia [aHR (95% CI)]
Age	66–69	70–79	≥80
No treatment	Ref	Ref	Ref
Treatment	0.58 (0.54–0.61)	0.58 (0.56–0.60)	0.60 (0.57–0.62)
P _interaction		.93	.45
Sex	Male	Female
No treatment	Ref
Treatment	0.60 (0.57–0.62)	0.56 (0.54–0.58)
P _interaction		.01
Race	White	Black	Asian	Other
No treatment	Ref	Ref	Ref	Ref
Treatment	0.61 (0.59–0.62)	0.50 (0.48–0.53)	0.51 (0.46–0.57)	0.62 (0.50–0.75)
P _interaction		<.001	.01	.86
Diabetes	No	Yes
No treatment	Ref	Ref
Treatment	0.59 (0.56–0.61)	0.57 (0.55–0.59)
P _interaction		.34