Renal Adverse Effect of Anagrelide in Patients with Myeloproliferative Neoplasms

Along with hydroxyurea, anagrelide has been widely used for the treatment of myeloproliferative neoplasms (MPNs). In contrast to hydroxyurea, anagrelide selectively inhibits megakaryocyte colony development and its cytoreductive effect relatively limited to platelets, hence, it usually used as a first line therapy for the patients with essential thrombocytosis (ET). The frequently reported adverse events of anagrelide are palpitation, headache, edema, and vague abdominal symptoms. Renal insufficiency as a complication of anagrelide treamtent is not well recognized. Some studies suggested that anagrelide has a possible relationship to renal failure, especially in the patients with preexisting renal diseases. A few cases of acute interstitial nephritis or renal tubular necrosis were reported sporadically. However, the relationship between anagrelide and renal insufficiency remain unclear, and its mechanism remains to be further elucidated. In the present study, we investigated the incidence and the characteristics of renal impairment in anagrelide-treated patients with MPNs.

Total 335 patients with thrombocythemia due to MPNs who showed normal renal function before starting treatment were enrolled. They were serially assessed renal function and serum potassium levels. Treatment modalities such as anagrelide, hydroxyurea, phlebotomy or combination were decided by the characteristics of presenting cytosis and patients' tolerability. If the patients showed renal impairment during the treatment period, other parameters such as co-morbidities, combined medication history, electrolytes imbalance, urine analysis, and imaging studies were fully assessed in order to find the existing causes of renal failure.

Of total enrolled 335 patients, 54.0% with ET, 33.4% with polycythemia vera (PV), 3.3% with primary myelofibrosis, 0.6% with chronic neutrophilic leukemia (CNL), and 6.6% with MPN, unclassifiable. Others were diseases categorized as a myelodysplastic (MDS)/MPN (1.5% with atypical chronic myeloid leukemia and 0.6% with chronic myelomonocytic leukemia). In terms of treatment modalities, 56.7% were anagrelide group (anagrelide alone, anagrelide+hydroxyurea, and anagrelide+phlebotomy), whereas 43.3% were non-anagrelide group (hydroxyurea alone and hydroxyurea+phlebotomy). The median age of anagrelide group was 61 years (ranges; 19–84 years) and non-anagrelide group was 57 years (ranges: 14–84 years). In anagrelide group, the median serum creatinine levels before starting treatment was 0.8 mg/dL (ranges: 0.5–1.3 mg/dL). In non-anagrelide group, median serum creatinine was 0.9 mg/dL (ranges: 0.4–1.3 mg/dL). After addressing the treatment, forty-six (24.2%) in anagrelide group revealed increases of serum creatinine (median: 1.5 mg/dL, ranges: 1.4–2.3) above the normal reference ranges. Median estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation in these patients was 39.5 mL/min/1.73 m² (ranges; 21.0–56.0). On the other hand, in non-anagrelide group, only 7.6% showed increases of serum creatinine (median 1.5 mg/dL, ranges: 1.4–2.0) and decreases of eGFR (median; 43 mL/min/1.73 m², ranges: 32–53) (P=0.000). The relative risk ratio (RR) for renal impairment of anagrelide use was 3.89 (C.I.: 1.94–7.83) (P=0.000). Median time to develop renal impairment from the start of anagrelide was 13.8 months (ranges; 0.2–53.4 months). In anagrelide group, 8.4% have diagnosed as diabetes mellitus (DM) before starting the anagrelide, however, the preexisting DM was not significantly related to the development of renal failure (RR=1.26, P=0.649). Of total 46 patients who showed renal impairment after anagrelide use, mild to moderate proteinuria (grade 1 or 2) were revealed in ten patients (21.7%). Furthermore, nine patients (19.6%) showed the features of hyperkalemic renal tubular acidosis which was charaterized by metabolic acidosis, hyperkalemia, and low transtubular potassium gradient (TTKG < 5).

In the present study, we suggested the possible casual relationship between anagrelide therapy and renal impairment. Although large randomized studies and more detailed analyses to find the underlying mechianisms may be warranted, caution and serial follow-up of renal function should be indicated in MPN patients with anagrelide treatment.

No relevant conflicts of interest to declare.