What are the causes of resistant hypertension?

Causes of Resistant Hypertension

Resistant hypertension is almost always multifactorial in etiology, requiring systematic evaluation to exclude pseudoresistance before identifying true contributing factors including lifestyle issues, interfering substances, secondary causes, and inadequate diuretic therapy. 1

Pseudoresistance (Must Be Excluded First)

Before diagnosing true resistant hypertension, you must rule out these common mimics:

• Poor medication adherence – accounts for approximately 50% of apparent treatment-resistant hypertension 1
• White coat hypertension – requires confirmation with out-of-office BP measurements or 24-hour ambulatory monitoring 1
• Improper BP measurement technique – including wrong cuff size or poor technique 1
• Suboptimal medication regimen – use of noncomplementary drug classes or inadequate dosing 1

Lifestyle and Dietary Factors

These modifiable factors are extremely common contributors:

• Obesity – one of the strongest risk factors for treatment resistance 1
• Excessive dietary sodium intake – promotes volume expansion and treatment resistance 1
• Heavy alcohol consumption – directly interferes with BP control 1
• Physical inactivity – lack of regular exercise contributes to resistance 1

Interfering Substances and Medications

Identify and discontinue or minimize these agents:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) – the most common interfering medication 1
• Oral contraceptives – can elevate BP significantly 1
• Sympathomimetic agents – including decongestants and stimulants 1
• Corticosteroids – both systemic and high-dose topical preparations 1
• Immunosuppressive agents – particularly calcineurin inhibitors 1
• Antidepressants – certain classes can interfere with BP control 1

Secondary Causes of Hypertension

Secondary hypertension is particularly common in resistant cases and should be systematically evaluated:

Renal Causes

• Chronic kidney disease (CKD) – impairs sodium excretion and is extremely common in resistant hypertension 1
• Renovascular disease – renal artery stenosis 1
• Renal parenchymal disease 1

Endocrine Causes

• Primary hyperaldosteronism – a leading secondary cause that is often underdiagnosed 1
• Pheochromocytoma/paraganglioma 1
• Cushing's syndrome 1
• Thyroid disorders – both hyper- and hypothyroidism 1

Other Secondary Causes

• Obstructive sleep apnea – present in a substantial proportion of resistant hypertension patients 1
• Coarctation of the aorta – particularly in younger patients 1

Volume Overload and Inadequate Diuretic Therapy

This is a critical and often overlooked cause:

• Refractory volume expansion – frequently related to inadequate diuretic treatment 1
• Insufficient diuretic dosing – failure to use optimal doses or appropriate diuretic class 1
• Wrong diuretic type – thiazides may be ineffective when eGFR <30 mL/min/1.73m² requiring loop diuretics 1
• Sodium retention from CKD – kidney disease fundamentally impairs sodium excretion 1

Patient Demographics and Comorbidities

Certain patient characteristics increase risk:

• Older age – elderly patients (≥75 years) have lower control rates 1
• African American race – higher prevalence of apparent treatment-resistant hypertension 1
• Male sex – associated with increased odds of resistance 1
• Diabetes mellitus – complicates BP management and increases resistance 1
• Long-standing, severe hypertension – with established target organ damage 1

Key Clinical Pitfalls

The most common error is failing to recognize that only 10-15% of apparent treatment-resistant hypertension represents true medication resistance – the majority is due to poor adherence, high sodium intake, or undiagnosed secondary causes. 1 Always confirm out-of-office BP measurements before intensifying therapy, as white coat effect is extremely common. 1 Additionally, inadequate diuretic therapy is frequently overlooked; volume expansion is a primary mechanism of resistance that requires aggressive diuretic optimization. 1

The 2019 KDOQI commentary emphasizes that resistant hypertension may not even be a relevant term for CKD patients, as kidney disease inherently complicates hypertension management through impaired sodium excretion. 1 In the CRIC Study, 40% of CKD patients had apparent treatment-resistant hypertension, which was associated with significantly higher cardiovascular risk and mortality. 1