Hyperuricemia is one of the common complications of hematologic malignancies, resulting from a high proportion of cellular turnover rate. In addition, cell lysis occurs during treatment with chemotherapy or cytoreductive agents not only can aggravate elevated serum uric acid (SUA) but also increase urine uric acid (UUA) excretion and acute uric acid nephropathy is possibly anticipated. Therefore, it is generally suggested that allopurinol should be prescribed in these patients to prevent acute uric acid nephropathy (1–4). Moreover, hyperuricemia has well-described reports on the association with physical illnesses such as hypertension, impaired fasting blood glucose and type 2 diabetes, metabolic syndrome, and coronary heart disease in previous studies (5–10). These comorbidities and SUA levels should be a concern, especially in individuals with hematologic malignancies. Although the tumor lysis syndrome (TLS) is the life-threatening complication, with a prevalence ranging from 6.1% to 27.8% in patients with acute leukemia and non-Hodgkin lymphoma, that results in hyperuricemia and acute kidney injury, the study on the risk factors of hyperuricemia or hyperuricosuria remains controversial (1–4). A 5.5% incidence of de novo kidney stones in patients with myeloproliferative and lymphoproliferative disorders after initiation of chemotherapy had been reported (11). Uric nephrolithiasis typically develops in patients who have acidified urine, hyperuricosuria, and low urine volume. It remains to be explored whether hematologic malignancies with a high tumor cell burden contribute to a significant subset with a lesser incidence of kidney stones (12, 13).

The prevalence of hyperuricemia in hematologic malignancies has been reported to range between 18.9 and 65.5% (1, 3, 4, 14–16). Moreover, studies on UUA excretion also showed conflicting results between uric acid hyperexcretion and uric acid underexcretions (16, 17). This study aimed to determine the prevalence and risk factors of hyperuricemia and hyperuricosuria in patients with previously untreated hematologic malignancies. The study specifically examined uric acid concentration and excretion within a defined group of hematologic malignancies characterized by subacute or chronic progression and proliferative behavior. It focused on two representative diseases: myeloproliferative neoplasms (myeloid lineage) and lymphomas (lymphoid lineage). The hypothesis centered on the possibility that these distinct malignancies may exhibit divergent uric acid metabolism due to underlying differences in their pathogenic mechanisms.

A total 192 patients were recruited, 27 patients were excluded, and of 165 patients (51.5% male) were enrolled in the study. Median (IQR) age and body mass index (BMI) were 55 years (45.5–64) and 21.2 kg/m² (19–23), respectively. Pre-existing comorbidities included diabetes mellitus in 4.8% and hypertension in 14.5%. Overall, prevalence of hyperuricemia was 43.6% (95%CI: 6.03–6.56) with median SUA of 6.3 mg/dl (4.6–8) prevalence of hyperuricosuria was 39.4% (95%CI: 518.52–596.27) with median 24-h UUA of 545 mg (365.4–991). The patients were separated by type of hematologic malignancies into lymphoma in 91 (55.2%) cases and MPN in 74 (44.8%) cases. Lymphoma patients had a median age of 60 years (51–69) with 84.6% of diffuse large B-cell lymphoma (DLBCL) and 15.4% of indolent lymphoma, while the median age of MPN patients was 48 years (39.7–58). Hypertension was slightly higher in lymphoma than in MPN patients (19.8% vs. 8.1%, p = 0.045). There was no difference in sex distribution, BMI, proportion of diabetes mellitus, and hemoglobin level between lymphoma and MPN patients. MPN patients (CML in 66.2%, ET in 17.6%, and PV in 16.2%) had significantly higher initial white blood cells count, platelet count, and serum LDH, while eGFR was significantly lower than patients with lymphoma. Hyperuricemia was observed in 20.9% (95%CI: 4.98–5.63) and 71.6% (95%CI: 7.59–8.26) of lymphoma and MPN patients (p = 0.018), respectively. Hyperuricosuria was detected in 9.9% (95%CI: 395.94–505.90) and 63.5% (95%CI: 902.1–1,013.13) of lymphoma and MPN patients (p = 0.005), respectively (Figure 1, Table 1).

Due to the difference in clinical characteristics and disease biology, the associated parameters of hyperuricemia and hyperuricosuria were separately analyzed between lymphoma and MPN patients. For lymphoma patients, the median SUA in the hyperuricemia group (n = 19) and in the normouricemia group (n = 72) was 7.9 mg/dL (7.2–8.3) and 4.6 mg/dl (3.3–5.7), respectively. DLBCL patients had a trend of slightly higher in proportion of hyperuricemia than patients with indolent lymphoma. There was no significant difference in clinical characteristics between lymphoma patients with and without hyperuricemia except that those who had hyperuricemia had a higher proportion of patients with impaired renal function (eGFR < 90 ml/min/1.73 m²) (73.6% vs. 44.5%, p = 0.035) and serum LDH ≥ 250 mg/dl (63.2% vs. 51.3%, p = 0.009). The proportion of patients with hyperuricosuria was also higher in patients with hyperuricemia than in the normouricemia group (57.9% vs. 4.2%, p < 0.001) (Table 2).

In MPN patients, the median SUA in the hyperuricemia group (n = 53) and in the normouricemia group (n = 21) was 8.9 mg/dl (8, 9) and 5 mg/dl (4.6–6). Among MPN patients with hyperuricemia, the median SUA levels were 9 mg/dl (8, 9) for CML, 8 mg/dl (7.6–8.8) for ET, and 8.9 mg/dl (8, 9) for PV, with no statistically significant differences between the groups. For MPN patients with hyperuricosuria, the median 24-h UUA excretion levels were 1,069 mg (980–1,175) for CML, 1,137 mg (856–1,179) for ET, and 1,090 mg (978–1,218) for PV, with no statistically significant differences between the groups. Hyperuricosuria was more prevalent in patients with hyperuricemia compared to those with normouricemia (75.5% vs. 52.4%, p = 0.027) (Table 3).

In the multivariable analysis, independent risk factors associated with hyperuricemia in patients with lymphoma were eGFR < 90 ml/min/1.73 m² (odds ratio (OR) 3.24, 95% confidence interval (CI) 1.95–11.07, p = 0.006) with an area under a receiver operating characteristics (AuROC) curve of 0.6462 (Figure 2) and serum LDH ≥ 250 mg/dl (OR 2.07, 95%CI 1.62-6.97, p = 0.039) with AuROC curve of 0.6404 (Figure 3). Hyperuricosuria was related to hyperuricemia in both lymphoma and MPN patients (Table 4, Supplementary Table S1).

Regarding hyperuricosuria, lymphoma patients with hyperuricosuria had a median 24-h UUA of 887.3 mg (772.8–1,049) compared to 389.6 mg (243.2–480.2) in patients with normouricosuria. Lymphoma patients with hyperuricosuria were younger (median age of 51.5 years vs. 61 years, p = 0.021), males predominant (85.7% vs. 42.9%, p = 0.009) with lower platelet count (median platelet 145 x 10⁹ vs. 251 x 10⁹, p = 0.019). Median serum LDH was higher in hyperuricosuria patients (597 U/L vs. 249 U/L, p = 0.013). The proportion of patients with hyperuricemia was higher in patients with hyperuricosuria than in the normouricosuria group (78.6% vs. 10.4%, p < 0.001) (Table 5).

Among MPN patients, those with hyperuricosuria had lower hemoglobin level (median hemoglobin level 9.4 g/dl vs. 12 g/dl, p = 0.006), higher white blood cells count (median WBC count 186.5 × 10⁹/L vs. 18.5 × 10⁹/L, p = 0.004), and lower platelet count (median platelet 521.9 × 10⁹/L vs. 655 × 10⁹/L, p = 0.017) compared to those with normouricosuria. For the MPN subtype, CML patients had a higher proportion of hyperuricosuria (78.4% vs. 39.1%, p = 0.002), while the ET patients had a lower proportion of patients with hyperuricosuria (9.8% vs. 34.8%, p = 0.013). MPN patients with hyperuricosuria had lower median eGFR (p = 0.034) but higher median serum LDH (702 U/L vs. 491 U/L, p = 0.003). Hyperuricemia was higher in patients with hyperuricosuria than in the normouricosuria group (78.7% vs. 56.5%, p = 0.037) (Table 6).

Independent risk factors for hyperuricosuria in lymphoma patients were male sex (OR 9.11, 95%CI 1.12–7.78, p = 0.038) and LDH ≥ 250 mg/dl (OR 2.37, 95%CI 1.56–14.29, p = 0.036) with AuROC curve of 0.6939 (Figure 4). However, hemoglobin level < 10 g/dl and serum LDH ≥ 640 mg/dl were independent risk factors for hyperuricosuria in MPN patients (OR 1.88, 95%CI 1.42–8.39, p = 0.045 with AuROC curve of 0.7165 and OR 6.21, 95%CI 1.49–25.74, p = 0.012 with AuROC curve of 0.7357) (Figures 5, 6). Hyperuricemia was the related factor hyperuricosuria in both MPN and lymphoma patients (Table 7, Supplementary Table S2).

This study found a 43.6% overall prevalence of hyperuricemia in hematologic malignancies, almost 3.5 times more common in MPN than in lymphoma patients. The independent risk factors for developing hyperuricemia in lymphoma patients were impaired renal function and elevated serum LDH. Moreover, hyperuricosuria was found in 39.4% of patients, almost 4.5 times more common in MPN than lymphoma patients. The independent risk factor of hyperuricosuria was anemia in lymphoma and elevated serum LDH in both of lymphoma and MPN patients.

The prevalence of hyperuricemia in this study was consistent with the previous reports (1, 3, 4, 14–16). One small-scale study enrolled 12 lymphoma patients with a 58.3% prevalence of hyperuricemia, and 41.6% had hyperuricosuria (14). Another study of uric acid metabolism, involving 186 patients with hematologic malignancies, including leukemia, MPN and multiple myeloma reported an overall prevalence of hyperuricemia of 65.5%. Notably, two-thirds of the patients with hyperuricemia in this study had MPN and CML, and there were no patients with lymphoma included in the study (15). A retrospective study from Japan included 418 hematologic malignancies patients (lymphoma in almost half of cases and leukemia in one-third) found the overall prevalence of hyperuricemia of 27.8% (23.6% in lymphoma, and 45.8% in CML), which showed a similar trend to our study. Hyperuricosuria was found in only 10%, all of whom were male patients with lymphoma and acute leukemia (16). Regarding hyperuricemia and tumor lysis syndrome in patients with acute leukemia and non-Hodgkin lymphoma, hyperuricemia ranged from 12.6% to 26.5%, with the development of tumor lysis syndrome occurring in about 15.9%−27.8% of cases (1, 3). In patients with MPN, specifically ET and PV, a previous study reported a hyperuricemia prevalence of 31% and demonstrated inferior thrombosis-free survival (TFS) in patients with SUA levels above 5.06 mg/dL (4). The prevalence of hyperuricemia in MPN patients from this study differed from our study, with a hyperuricemia of 71.6%. This variation may be attributed to the slightly different SUA cutoff defining hyperuricemia and the inclusion of patients with CML, which accounted for 66.2% of MPN cases in our current study. The higher prevalence of hyperuricemia in MPN in our study may stem from the elevated white blood cell count seen in CML, reflecting a higher tumor burden and uric acid load. This study found that lower hemoglobin levels and high LDH were independent risk factors for hyperuricosuria. The exploratory hypothesis was supported by an increase in cell turnover, ineffective erythropoiesis, and reduced renal clearance, which contributed to the accumulation of uric acid and increased excretion of uric acid in the urine.

For lymphoma patients, hyperuricosuria was observed in only 15.4%. Our findings demonstrated that two-thirds of MPN patients had hyperuricosuria, with the majority of them having CML. Therefore, MPN patients with anemia and high serum LDH who had hyperuricemia should be considered the uric acid lowering therapy to prevent further complications arising from elevated serum uric acid levels.

There were several limitations in this study. As shown in this study, a separate analysis of prevalence and associated risk factors on uric profiling was performed because of the difference in the natural course of the disease and clinical characteristics between lymphoma and MPN. Therefore, it may raise the issue of an underpowered study from the small sample size in each group in terms of associated risk factors analysis. Patients with acute leukemia were also excluded because our study group prioritized emergency treatment for patient safety, particularly concerning tumor lysis syndrome. Typically, allopurinol is administered before commencing treatment in such cases. Furthermore, a single center with a cross-sectional study design may limit the generalizability of the findings. Then, the further longitudinally prospective study with the collaboration of multicenter on hematologic malignancy patients, including a matched-control group, with comprehensive monitoring of serum uric, urate excretion, and clinical correlation, would be warranted to make causal inferences. Additionally, there was a lack of data on the potential genetic alterations of a group of genes related to the net balance of renal urate absorption and secretion that might influent SUA and UUA (25). However, the strength of our study compared to all the previous studies was the analytically addressed risk factors of hyperuricemia and hyperuricosuria. The various conditions and medications that could alter SUA and UUA excretion were excluded to ensure that SUA and UUA were not interfered with by other factors, which were not mentioned in many previous studies. Also, those patients who were found to have eGFR < 60 ml/min/1.73 m² after enrollment were excluded to ensure that those who participated in this study did not have impaired renal function that could interfere with SUA and UUA excretion.

This study found that almost half of the patients with hematologic malignancies (predominant with lymphoma and MPN) had hyperuricemia, and only one-third had hyperuricosuria (the majority being MPN and CML). Lymphoma patients with lower eGFR and high serum LDH were at risk of hyperuricemia. Elevated LDH was related to hyperuricosuria in both lymphoma and MPN patients. These findings may have implications for managing and treating hyperuricemia in patients with hematologic malignancies.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Research Ethics Committee 4, Faculty of Medicine, Chiang Mai University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

TK: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing—review & editing. TR: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing. TP: Writing—review & editing. NH: Writing—review & editing. PP: Writing—review & editing. SH: Writing—review & editing. CC-A: Writing—review & editing. ER: Writing—review & editing. AT: Writing—review & editing. LN: Writing—review & editing. WL: Conceptualization, Methodology, Writing—review & editing.