Does sirolimus (rapamycin) induce hypertension?

From the Guidelines

Sirolimus is not induced by press, but rather it is an immunosuppressant medication that can cause various side effects, including hypertension, which is a concern in terms of morbidity, mortality, and quality of life. Sirolimus works by inhibiting the mammalian target of rapamycin (mTOR) pathway, which regulates cell growth and proliferation 1. It is primarily used to prevent organ rejection in transplant patients, particularly kidney transplants, and is sometimes used in drug-eluting stents for coronary artery disease. The typical oral dosing for adults after kidney transplantation is a 6 mg loading dose followed by 2 mg daily maintenance, adjusted based on blood levels 1. Sirolimus requires regular blood level monitoring to maintain therapeutic concentrations while avoiding toxicity.

Key Points to Consider

• Side effects may include increased cholesterol, decreased blood cell counts, mouth ulcers, and impaired wound healing 1.
• Hypertension and peripheral edema are adverse effects from trials where sirolimus was used in combination with cyclosporine 1.
• Elevations in serum creatinine level were seen when used in combination with cyclosporine, but the incidence of this adverse reaction was significantly lower in a series of patients using sirolimus alone 1.
• Patients experienced diarrhea, dyspepsia, nausea, vomiting, and constipation during clinical trials 1.
• Sirolimus has multiple hematologic effects, including anemia and thrombocytopenia 1.
• Hyperlipidemia and hypercholesterolemia are dose-related effects of sirolimus 1.
• Monitoring of CBC counts, creatinine, and BP is recommended for patients who undergo mTOR therapy 1.
• For patients who undergo sirolimus therapy, monitoring of drug concentration is recommended 1.

Recommendations for Clinical Practice

• Monitoring for hyperlipidemia is recommended for patients who undergo mTOR therapy 1.
• Administration of sirolimus during the early perioperative period is contraindicated due to the risk of airway dehiscence 1.
• Consideration of dose adjustments or an alternative therapy to lower the risk of poor wound healing is suggested for patients who undergo sirolimus therapy and are at risk 1.
• An evaluation for sirolimus-induced pulmonary toxicity is recommended for patients who develop new or worsening respiratory symptoms or signs 1.

From the Research

Sirolimus and Blood Pressure

• Sirolimus-based therapy was associated with a lower incidence of treatment-emergent hypertension (47.5% vs 29.6%, P <.024) compared to cyclosporine-based therapy 2.
• However, another study found that sirolimus can induce focal segmental glomerulosclerosis (FSGS) de novo, which may be associated with hypertension 3.

Mechanism of Sirolimus-Induced Hypertension

• The exact mechanism of sirolimus-induced hypertension is not fully understood, but it may be related to its effects on lipid metabolism and renal function 4.
• Sirolimus has been shown to alter the insulin signaling pathway, leading to increased adipose tissue lipase activity and/or decreased lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride and hypertriglyceridemia 4.

Comparison with Other Immunosuppressive Agents

• Cyclosporin and tacrolimus, two other immunosuppressive agents, have been shown to be nephrotoxic and induce arterial hypertension 5.
• Sirolimus, on the other hand, does not inhibit calcineurin and provides immunosuppression without nephrotoxicity, making it a potentially better option for patients with hypertension 5.

Clinical Implications

• The use of sirolimus in patients with hypertension requires careful monitoring of blood pressure and renal function 2, 3.
• The benefits and risks of sirolimus therapy should be weighed carefully in patients with hypertension, and alternative immunosuppressive agents may be considered if necessary 5, 6.