Treating Hypertension in Transplant Recipients: Chlorthalidone versus Amlodipine

In kidney transplantation recipients, hypertension following the transplant has been shown to be an independent risk factor for transplant failure. Hypertension after transplantation is also associated with increased risk for cardiovascular disease and mortality. Contributors involved in development of hypertension after transplant include donor, recipient, and transplantation factors. Patients treated with calcineurin inhibitors (CNIs) have been shown to have increased incidence of hypertension following the introduction of cyclosporine.

Mechanisms including systemic and renal vasoconstriction contribute to CNI-induced hypertension, possibly through endothelin 1, and impaired vasodilation, explaining the efficacy of dihydropyridine calcium channel blockers (CCBs) for the treatment of CNI-induced hypertension. However, CNI-induced hypertension has also been shown to be salt sensitive. The salt sensitivity of CNI-induced hypertension has recently been linked to the activation of one specific sodium transporter in the kidney, suggesting that thiazide diuretics that block the sodium-chloride cotransporter (NCC, encoded by the SLC12A3 gene) may be effective in treating CNI-induced hypertension.

In one study, results demonstrated that thiazide diuretics did effectively lower blood pressure in kidney transplant recipients; however, treatment was associated with higher incidences of hyperkalemia and hypokalemia. Thiazide diuretics may be used infrequently in this patient population due to concerns related to efficacy at lower estimated glomerular filtration rates or adverse events such as gout and glucose intolerance. Arthur D. Moes, MD, and colleagues in The Netherlands recently conducted a study designed to analyze the effects of thiazide inhibitors in kidney transplant recipients using tacrolimus. The researchers were testing the hypothesis that chlorthalidone is equally effective as amlodipine for the treatment of hypertension following kidney transplantation. They reported results in the American Journal of Kidney Diseases [69(6):976-804].

The study was a randomized noninferiority crossover trial, with a margin of noninferiority of –2.8 mm Hg. The primary outcome of interest was average daytime (9 am to 9 pm) ambulatory systolic blood pressure.

Patients meeting eligibility criteria were randomly assigned to start with chlorthalidone, 12.5 mg, or amlodipine, 5-10 mg, for 8 weeks, followed by a 2-week washout period, and then 8 weeks with the remaining drug. There were six scheduled study visits: the start and end of each treatment period and 2 weeks after starting each drug. Blood pressure was measured every 5 minutes for 30 minutes at the 2-week visit.

Eighty-eight patients underwent the initial ambulatory blood pressure measurement. Of those, 56% (n=49) had daytime systolic blood pressure >140 mm Hg. Those 49 patients started in the study. A total of 41 patients completed the study and were included in the analysis.

Five patients stopped the study during the chlorthalidone treatment for adverse events; one patient stopped during the amlodipine treatment for an adverse event, and two stopped during the washout period.

Of the 49 patients who completed the study, 76% had received a living donor kidney transplant and 88% had tacrolimus and mycophenolate mofetil as the immunosuppressive regimen. None of the patients used glucocorticoids. Rates of dose escalation were similar: 37% (n=15) for amlodipine versus 41% (n=17) for chlorthalidone; P=.8). Average daily drug doses were 6.4 mg for amlodipine and 16.4 mg for chlorthalidone.

Both study drugs reduced daytime systolic blood pressure (amlodipine: from a mean of 150 to 137 mm Hg; chlorthalidone: from a mean of 151 to 141 mm Hg). There was no statistical difference in blood pressure response between the two drugs. Chlorthalidone appeared to cause a carry-over effect (lower baseline systolic blood pressure for patients receiving amlodipine as second treatment).

Despite similar blood pressure responses, there was significant reduction in proteinuria with chlorthalidone (median change, 169 to 116 mg/g; mean 32% reduction vs 4% increase during amlodipine). In addition, urinary calcium was nearly halved during chlorthalidone, whereas it increased during amlopidine. Estimated glomerular filtration rate (eGFR)decreased during treatment with chlorthalidone (from 58 to 50 mL/min/1.73 m2); eGFR increased during treatment with amlopidine (from 54 to 58 mL/min/1.73 m2). However, in the 23 patients who completed treatment order two (first chlorthalidone) eGFRs normalized during the washout and amlopidine treatment periods. Five patients who continued treatment with chlorthalidone following completion of the study had initial decreases in eGFR (from 75 to 64 mL/min/1.73 m2) that later stabilized (65 mL/min/1.73 m2 after a mean of 21 weeks of treatment with chlorthalidone).

Treatment with chlorthalidone also increased serum uric acid levels (without attacks of gout) and levels of hemoglobin A1c. Treatment with amlodipine increased tacrolimus predose concentrations.

With the exception of physician-assessed edema, both drugs were well tolerated. Physician-assessed edema increased during treatment with amlodipine from 10% to 34%, but decreased during chlorthalidone treatment from 22% to 10%. No acute rejections were diagnosed or treated during the study period.

Limitations cited by the researchers included the open-label design and the lack of an intention-to-treat analysis. In addition, many eligible patients declined to participate in the study due to the four ambulatory blood pressure monitoring requirements, limiting the generalizability of the findings.

In summary, the researchers said, “Both amlodipine and chlorthalidone are effective antihypertensive drugs after kidney transplantation; chlorthalidone may be preferable in patients with proteinuria or edema. Combination therapy with half doses of each agent may also be an interesting approach, which requires future study.”

Takeaway Points

  1. Chlorthalidone is effective in treating hypertension, but there are few data on its efficacy and safety in recipients of kidney transplant.
  2. Researchers in The Netherlands conducted a randomized noninferiority crossover trial to compare the effectiveness of chlorthalidone with that of amlodipine for treatment of hypertension in a population of kidney transplant recipients.
  3. Both drugs were effective antihypertensive agents following kidney transplantation; chlorthalidone may be preferable in patients with proteinuria or edema.