Intervention: ISOSORBIDE DINITRATE
Trial phase: Phase 4
ATC code: C01DA08 | C01DA58 | C05AE02
SMILES: [H][C@]12OC[C@@H](O[N+](=O)[O-])[C@@]1([H])OC[C@@H]2O[N+](=O)[O-]
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 7
Group description: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.

Allowable Dosage Forms:

ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day

Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.

Target Dose:

Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day

Allowable Dosage Forms:

ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day

Dose Titration:

ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.
Eligibility criteria:
Inclusion Criteria

Maintenance hemodialysis therapy for end-stage renal disease
Age 18-85 years
≥ 90 days since dialysis initiation
Ability to provide informed consent
Pre-dialysis seated systolic blood pressure measurements must be ≥ 120 mm Hg in the 2 weeks before enrollment and on the day of randomization.

Exclusion Criteria

Serum potassium ≥6.5 mEq/L within 2 months prior to screening
Unscheduled dialysis for hyperkalemia within the 3 months prior to screening
Hypotension defined as pre-dialysis SBP <100 mm Hg (seated measurement) within 4 weeks prior to enrollment
Recurrent intra-dialytic hypotension, defined as systolic blood pressure <80 mm Hg during ≥3 dialysis sessions per 30-day rolling period or treatment for either hypotension or symptoms of hypotension if systolic blood pressure is < 100 mm Hg during ≥3 dialysis sessions per 30-day rolling period.
Mitral valve repair or replacement
Severe mitral valve disease by echocardiography, coronary angiography or cardiac magnetic resonance imaging
Prior coronary artery bypass graft
Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another dialysis unit within 6 months
Expected survival < 6 months
Allergy to study medications (ISD, HY, adenosine/diprimidole)
Active use of sildenafil, vardenafil or tadalafil
History of severe aortic stenosis or other cause of LV outflow obstruction
Pregnancy, anticipated pregnancy, or breastfeeding, confirmed by serum pregnancy test on the day of PET scan
Incarceration
Participation in another intervention study
Use of monoamine oxidase inhibitors

Contraindication to adenosine including

2nd or 3rd degree heart block, sick sinus syndrome or symptomatic bradycardia (without a functioning pacemaker)
moderate or severe asthma
chronic obstructive pulmonary disease
Active use of any of the study medications unless participant and physician willing to discontinue prior to enrollment.