Background and objectives

Secondary hyperparathyroidism (SHPT) can lead to significant morbidity, mortality, and additional healthcare resource utilization in chronic kidney disease (CKD) stage 5. The objective of this study was to examine healthcare costs and utilization, and the risks of dialysis or mortality, among pre-dialysis CKD patients with and without SHPT.

Research design and methods

This retrospective cohort study examined insurance claims from 66 644 adult, pre-dialysis, CKD patients with and without SHPT during a 72-month period. Annualized estimates of healthcare costs and utilization, and disease progression to dialysis or death following index CKD diagnosis were compared.

Results

Post-index annualized costs and inpatient healthcare resource utilization was higher in those with SHPT in both unadjusted and adjusted (controlling for gender, age, plan type, payer type, geographic region, physician specialty, pre-index co-morbidities, and pre-index total healthcare costs), and unmatched and matched analyses. Kaplan-Meier analysis demonstrated that the rate of progression to dialysis or death was higher for CKD with SHPT compared to CKD without SHPT, and Cox proportional hazard models suggested that CKD patients with SHPT were more than four to five times as likely to initiate dialysis or die as compared to CKD without SHPT.

Conclusion

SHPT in pre-dialysis CKD patients is associated with significantly greater healthcare costs, inpatient hospitalizations, and a faster rate of disease progression compared to pre-dialysis CKD without SHPT. Since observational studies are designed to demonstrate associations rather than causality, further investigation is required to confirm these findings.

Background/aims

The objective of this study was to examine health care costs and utilization and the risks of dialysis or mortality among diabetic predialysis chronic kidney disease (CKD) patients with and without secondary hyperparathyroidism (SHPT).

Methods

This retrospective, matched cohort study examined insurance claims from 703 adult diabetic predialysis CKD patients with and without SHPT during a 72-month follow-up period. Annualized estimates of health care service utilization, costs and disease progression to dialysis or death following index CKD diagnosis were compared.

Results

Preindex (baseline) characteristics were similar between the cohorts. Postindex numbers of prescription utilization, outpatient service utilization and hospitalizations were all higher (p < 0.0001) in diabetic CKD patients with SHPT compared to those without SPHT in both unadjusted and adjusted analyses even after multivariate adjustment for known confounders. The rate of progression to dialysis or death was higher for diabetic CKD patients with SHPT compared to those without SPHT. Those with SHPT were at higher risk of requiring dialysis treatment [hazard ratio (HR) = 6.7; 95% confidence interval (CI) = 4.3-10.6] and death (HR = 2.3; 95% CI = 1.1-4.9) compared to those without SHPT.

Conclusion

In diabetic predialysis CKD patients, the presence of SHPT is associated with significantly greater health care resource utilization and costs, and a faster rate of disease progression.

Heart failure (HF) is characterized by global alterations in myocardial DNA methylation, yet little is known about the epigenetic regulation of the noncoding genome and potential reversibility of DNA methylation with left ventricular assist device (LVAD) therapy. Genome-wide mapping of myocardial DNA methylation in 36 patients with HF at LVAD implantation, 8 patients at LVAD explantation, and 7 nonfailing (NF) donors using a high-density bead array platform identified 2,079 differentially methylated positions (DMPs) in ischemic cardiomyopathy (ICM) and 261 DMPs in nonischemic cardiomyopathy (NICM). LVAD support resulted in normalization of 3.2% of HF-associated DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated (HTRA1, FBXO16, EFCAB13, and AKAP13) or hypermethylated and downregulated (TBX3) in HF. A potentially novel cardiac-specific super-enhancer long noncoding RNA (lncRNA) (LINC00881) is hypermethylated and downregulated in human HF. LINC00881 is an upstream regulator of sarcomere and calcium channel gene expression including MYH6, CACNA1C, and RYR2. LINC00881 knockdown reduces peak calcium amplitude in the beating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These data suggest that HF-associated changes in myocardial DNA methylation within coding and noncoding genomes are minimally reversible with mechanical unloading. Epigenetic reprogramming strategies may be necessary to achieve sustained clinical recovery from heart failure.

Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line. Similarly, mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls. High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype. Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation.