Treatment of Essential Thrombocythemia with Anagrelide Is Associated with an Increased Risk of Worsened Kidney Function

Abstract

Background and Purpose: When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation. Experimental Approach: The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment. Key Results: A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m2 [interquartile range (IQR) (−4)–(+7)] in the HU group vss. median −13 mL/min/1.73 m2 [IQR (−18)–(−6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17–15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m2 occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21–3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998). Conclusions and Implications: The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function.

Presence and Onset of Chronic Kidney Disease as a Factor Involved in the Poor Prognosis of Patients with Essential Thrombocythemia

“…Since the entity “MPN-related glomerulopathy” was reported in 2011 [ 24 ], the association between MPNs and renal hypofunction has attracted attention. The incidence of CKD at the time of ET diagnosis is reportedly higher than in the general population [ 25 , 26 ], being 12.9 to 28.9% [ 13 , 15 – 17 , 27 , 28 ]. The incidence of CKD in this cohort (28.8%) was similar to that in Europe, although it is slightly lower at approximately 15% in Asians.…”

Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules

“…A recently published longitudinal study ( n = 150 patients) ( Mazzucconi et al, 2020 ) have showed a response rate of 85.4%; ADRs included palpitations, peripheral vasodilation, anemia, diarrhea, gastric distress and thrombotic events, suggesting the importance of assessing thrombotic risk and monitoring cardiac function. The drug was also found to be characterized by nephrotoxicity, increasing the risk of renal function impairment, according to a recent retrospective study ( Kwiatkowski et al, 2021 ).…”

Modifying the Effects of Cytoreductive Drugs on Kidney Function in Myeloproliferative Neoplasms

“…We read the recent article by Kwiatkowski et al [1] investigating the impact of hydroxyurea (HU) and anagrelide (ANA) treatment on kidney function in essential thrombocythemia (ET) patients with great interest. This retrospective analysis performed on 310 ET patients demonstrated that the use of ANA may be associated with a higher risk of worsening of kidney function than the use of HU, independently of the presence of arterial hypertension and the type of driver mutation (with calreticulin-mutated patients potentially having worse kidney outcomes) [1]. The authors should be commended for their effort, as several recent studies have shown that chronic kidney disease (CKD) can be found in approximately one-fourth of patients with BCR-ABL1-negative myeloproliferative neoplasms [2-5].…”

“…Although ET patients treated with HU or ANA in the study by Kwiatkowski et al [1] had similar clinical responses to both cytoreductive treatments (overall response 85.31 vs. 84.85%, respectively, p = 0.915), their kidney outcomes significantly differed, with ANA-treated patients having worse 6-month kidney outcomes. These observations suggest that the well-known ANA-related circulatory side effects [9] could also have a role in promoting kidney damage.…”

“…Of note, the ACE-i have been shown to have the potential to suppress clonal erythropoiesis in PV, suggesting a cytoreductive potential of these drugs [12]. Notably, in the study by Kwiatkowski et al [1], HU-treated patients more often had arterial hypertension (49.76 vs. 38.38%, p = 0.061), which was also a risk factor for worsening of kidney function in the multivariate analysis (OR 2.20, p = 0.006). Although no differences in age between the HU and ANA users were found in this particular study (66 vs. 64 years of age, respectively, p = 0.122), ANA is usually more often prescribed to younger ET patients due to its unfavorable cardiovascular side effects; thus, these patients are probably less likely to have arterial hypertension and to use ACE-i.…”