Which immunosuppressants (e.g. calcineurin inhibitors, corticosteroids) can cause hypertension?

Immunosuppressants That Cause Hypertension

Calcineurin inhibitors (cyclosporine and tacrolimus) and corticosteroids are the primary immunosuppressants that cause hypertension, with cyclosporine causing more severe hypertension than tacrolimus. 1

Calcineurin Inhibitors

Cyclosporine

• Cyclosporine is associated with a higher incidence of hypertension (25-82%) compared to tacrolimus (17-64%) following transplantation. 1
• Cyclosporine causes hypertension through multiple mechanisms including renal vasoconstriction, sympathetic nervous system stimulation, sodium retention, and imbalance of vasoactive substances (increased endothelin, decreased nitric oxide). 1, 2
• The FDA drug label for cyclosporine lists hypertension as occurring in 13-53% of transplant patients depending on organ type. 3
• Cyclosporine increases activity of the thiazide-sensitive sodium-chloride cotransporter through effects on WNK and SPAK kinases, leading to sodium retention. 2

Tacrolimus

• Tacrolimus causes hypertension less frequently than cyclosporine but remains a significant cause, with incidence of 17-64% in liver transplant recipients. 1
• The FDA drug label for tacrolimus specifically warns about high blood pressure as a serious side effect requiring monitoring. 4
• Tacrolimus shares similar mechanisms with cyclosporine including renal vasoconstriction and sodium retention, though the magnitude is generally less. 2, 5
• The 2017 ACC/AHA guidelines recommend considering conversion from cyclosporine to tacrolimus as tacrolimus may be associated with fewer effects on blood pressure. 1

Corticosteroids

Systemic Corticosteroids (Prednisone, Prednisolone, Methylprednisolone, Dexamethasone)

• Corticosteroids are well-established causes of hypertension in transplant recipients and other patients requiring immunosuppression. 1
• The 2017 ACC/AHA guidelines explicitly list systemic corticosteroids among drugs that affect blood pressure and recommend avoiding or limiting use when possible. 1
• Corticosteroids cause hypertension through mineralocorticoid-like effects, direct increase in cellular potassium efflux, and promotion of sodium retention. 6
• The FDA drug label for prednisone warns about increased risk of hypertension, particularly in elderly patients. 7
• Corticosteroids can exacerbate gestational diabetes and cause hypertension during pregnancy in transplant recipients. 1

mTOR Inhibitors

Sirolimus (Rapamycin)

• Sirolimus has significant effects on blood pressure, particularly when used in combination with calcineurin inhibitors. 1
• The interaction between calcineurin inhibitors and sirolimus promotes hypertension beyond the effect of either agent alone. 8
• Sirolimus also causes dyslipidemia which contributes to overall cardiovascular risk. 1

Mechanisms of Immunosuppressant-Induced Hypertension

Renal Mechanisms

• Calcineurin inhibitors cause renal vasoconstriction and long-term vascular structural changes that are among the most important mechanisms of post-transplant hypertension. 1
• Impaired renal function from immunosuppressants leads to relative salt and water retention even in successfully transplanted kidneys. 1
• Calcineurin inhibitors increase activity of renal sodium transporters, specifically the thiazide-sensitive sodium-chloride cotransporter. 2

Vascular Mechanisms

• Calcineurin inhibitors interfere with the balance of vasoactive substances, increasing endothelin (vasoconstrictor) and decreasing nitric oxide (vasodilator). 2, 5
• These agents cause direct vasoconstriction through sympathetic nervous system stimulation. 1, 5

Metabolic Mechanisms

• Corticosteroids promote atherosclerosis, diabetes, and ischemic heart disease, all of which contribute to hypertension. 6
• The combination of immunosuppressants often causes multiple metabolic derangements (diabetes, dyslipidemia) that compound hypertension risk. 1

Clinical Implications

Prevalence in Transplant Populations

• Hypertension prevalence in renal transplant recipients exceeds 65%, with some studies reporting up to 90-100% as calcineurin inhibitors have gained widespread use. 1, 5
• Hypertension is less common in non-renal transplant recipients but still represents a significant complication. 1
• Nocturnal hypertension and reversal of diurnal blood pressure rhythm may be present in transplant patients, requiring ambulatory blood pressure monitoring for accurate assessment. 1

Impact on Outcomes

• Observational studies suggest that hypertension correlates with deterioration in graft function, making blood pressure control critical for transplant success. 1
• The high risk of graft occlusion and cardiovascular events suggests blood pressure should be lowered to <130/80 mmHg in transplant recipients. 1

Common Pitfalls to Avoid

• Do not assume all immunosuppressants have equal hypertensive effects—cyclosporine causes significantly more hypertension than tacrolimus. 1, 9
• Avoid overlooking the additive effects when multiple immunosuppressants are used together (e.g., calcineurin inhibitors plus corticosteroids plus mTOR inhibitors). 1, 8
• Do not forget that immunosuppressant-induced hypertension requires combination antihypertensive therapy in almost all patients due to the difficulty of blood pressure control. 1
• Remember that reducing or withdrawing corticosteroids can improve blood pressure control and should be considered in consultation with the transplant center. 1