Secondary hyperparathyroidism (SHPT) and hyperphosphatemia are independently associated with the progression of chronic kidney disease (CKD) and the incidence of cardiovascular events (CVEs) in patients with CKD, according to findings published in Nephrology Dialysis Transplantation. Researchers indicated that the parathyroid hormone (PTH) and phosphate levels of patients with CKD should be maintained within normal ranges to decrease CKD progression and CVE incidence.
SHPT (defined in this study as patients with excessive PTH levels or receiving treatment with PTH-reducing agents) is a complication of CKD associated with alterations in calcium and phosphate that have been further associated with increased morbidity and mortality. Prior studies have not illuminated whether negative outcomes associated with SHPT are confounded by these factors.
Investigators enrolled a cohort of patients with CKD (N=2445; 950 [38.9%] stage 3, 612 [25.0%] stage 4, 195 [8.0%] stage 5, and 688 [28.1%] on dialysis) without previous CVE from the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study.
The primary study objective was to assess whether the potential independent effects of SHPT on the risk for CKD progression and CVE incidence in CKD patients act as effect modifiers. The effects of hypercalcemia and hyperphosphatemia were also assessed. Patient risk of suffering a CVE or CKD progression was determined using multivariate logistic and Fine and Gray regression analyses.
SHPT prevalence within the cohort was 65.6% (95% CI, 63.6%-67.6%). For CKD 3, the prevalence was 54.7% (95% CI, 51%-58.2%), it was 74.7% (95% CI, 70.9%-78.2%) for CKD 4, 71.4% (95% CI, 64.3%-77.6%) for CKD 5, and 68.6% (95% CI, 64.9%-72.1%) for participants on dialysis; 301 (23.5%) of the 1283 participants who had data on CKD progression presented disease progression, and 203 CVEs from the entire subcohort of 2445 participants were recorded in the 4 years of follow-up.
Participants with SHPT at baseline were more likely to show progression of CKD after 2 years and a CVE or a kidney transplant. These patients were also more likely to be women, to have a higher body mass index (BMI), to be at a more advanced CKD stage, and to present micro- or macroalbuminuria, and to have hyperphosphatemia.
Patients with SHPT also had lower 25(OH)D and calcium levels, lower total and low-density lipoprotein cholesterol, and higher high-sensitivity C-reactive protein (hsCRP). Crude analysis showed that variables associated with CKD progression and worse outcomes after 2 years were a history of hypertension or higher systolic or diastolic blood pressure, macroalbuminuria, and being in a more advanced CKD stage, with SHPT at baseline and hyperphosphatemia.
Bivariate analysis showed that variables associated with higher CV risk were being a man, being a current or former smoker, having diabetes, having hyperphosphatemia, having macroalbuminuria, and being on dialysis with SHPT. Additional factors increasing cardiovascular risk were being older and having higher levels of glucose, hsCRP, and systolic blood pressure, and having lower levels of 25(OH)D and high-density lipoprotein cholesterol.
After conducting multivariable logistic regression analysis for CKD progression, researchers showed that in any model tested, having SHPT and hyperphosphatemia at baseline were independently associated with CKD progression after 2 years. There were no significant interactions seen between SHPT presence and hypercalcemia or hyperphosphatemia.
In the crude analysis, the multivariable Fine and Gray model showed that baseline presence of SHPT and hyperphosphatemia were associated with a higher risk of having a CVE after 4 years. This remained true after adjusting for age and sex.
The trend for SHPT to increase CVE risk remained similar in the fully adjusted model. No significant interactions were seen between SHPT presence and hypercalcemia or hyperphosphatemia.
The study was limited by a lack of data on fibroblast growth factor 23 (FGF23), which could explain some residual effects, but the NEFRONA study design prevented the gathering of fasted samples. Because CKD progression assessment was made at a fixed point, only odds could be calculated instead of hazards. Nevertheless, the large number of patients with longitudinal observations did allow for investigators to control for multiple confounders.
Nonetheless, these results suggest that SHPT and hyperphosphatemia are independently associated with CKD progression and CVE.
“The reduction of both PTH and phosphate levels could be needed in order to improve the prognosis of CKD patients,” the study authors noted.
Disclosure: The NEFRONA study was supported by ABBVIE. The present analysis was supported by VIFOR Pharma. Please see the original reference for a full list of authors’ disclosures.
Bozic M, Diaz-Tocados JM, Bermudez-Lopez M, et al. Independent effects of secondary hyperparathyroidism and hyperphosphatemia on chronic kidney disease progression and cardiovascular events: an analysis from the NEFRONA cohort. Nephrol Dial Transplant. Published online May 21, 2021. doi:10.1093/ndt/gfab184