Fatal renal diseases among patients with hematological malignancies: A population‐based study

Abstract Patients with hematological malignancies might be at high risk for renal diseases as evidenced by earlier studies. We aim to investigate the mortality and risk factors of deaths due to renal diseases in this population. A total of 831 535 patients diagnosed with hematological malignancies in the Surveillance, Epidemiology, and End Results (SEER) database in the United States from 1975 to 2016 were identified. Standardized mortality ratio (SMR) was evaluated based on the general population's mortality data gathered by the National Center for Health Statistics. The mortality rate associated with renal diseases was 94.22/100 000 person‐years among patients with hematological malignancies (SMR = 3.59; 95% CI, 3.48‐3.70]). The highest mortality rate of dying from renal diseases was observed among multiple myeloma (MM) patients (307.99/100 000 person‐years; SMR = 7.98; 95% CI, 7.49‐8.50), followed by those with chronic myeloid leukemia (142.57/100 000 person‐years; SMR = 6.54; 95% CI, 5.63‐7.60) and chronic lymphocytic leukemia (103.66/100 000 person‐years; SMR = 2.51; 95% CI, 2.27‐2.77). The SMRs increased with time and were found to be the highest 10 years after cancer diagnosis. Independent predictors associated with death from renal diseases were found to be older age, male gender, blacks, unmarried, and MM, using the Cox proportional hazards model. We call for enhanced coordinated multidisciplinary care between hematologists and nephrologists to reduce the mortality rate of renal diseases among patients with hematological malignancies.

31% risk of developing AKI within 5 years, respectively [4]. Another investigation comprising 163 071 cancer patients in Ontario, Canada evidenced that MM (26%) and leukemia (15%) patients exhibited a relatively high 5-year incidence of developing AKI [5]. The occurrence of kidney diseases influences the treatment strategy, extends the period of hospital stay, decreases the patient's complete remission rate, and amplifies both treatment cost as well as mortality rate [6][7][8].
Earlier studies have investigated and categorized the pathogenesis of nephropathy among patients with hematological malignancies into three groups: the first category comprises nonspecific factors such as hypoperfusion; the second one involves the infiltration of tumors such as lymphoma or acute leukemia; and the third is related to therapies such as nephrotoxicity of chemotherapy and antibiotics [9]. In addition, cast nephropathy in patients suffering from MM may result in proteinuria and nephrotic syndrome owing to the deposition of light chain proteins [10].
This study was conducted to comprehensively analyze death due to renal diseases among patients with hematological malignancies involving a large population-based cohort. The mortality rate due to renal diseases among patients with hematological malignancies was evaluated, and subgroups of patients linked to a greater risk of dying from renal diseases were identified.

Data sources
This retrospective study was performed to identify patients suffering from hematological malignancies, the data for which were used from the Surveillance, Epidemiology, and End Results (SEER) database that documents information on cancer survival and incidence from population-based cancer registries, covering approximately 26% of the US population [11]. The "public use" version of the database was

Study variables
Variables extracted from the SEER database included sex (female and male); race (White, Black, and other including unknown); marital status (married; unknown; and unmarried including single, separated, divorced, widowed, unmarried, or domestic partner); age

Statistical analysis
The number of deaths caused by renal diseases divided by personyears of survival was calculated as the mortality rate among cancer

RESULTS
Thus analyzed data revealed that 4005 deaths occurred due to renal diseases among 831 535 patients suffering from hematological malignancies followed for 4 253 502 person-years (

Characteristics linked to higher mortality rate due to renal diseases
As patients suffering hematological malignancies grew older, the mortality rate due to renal diseases raised, but the SMR was observed TA B L E 2 Mortality due to renal diseases in patients with hematological malignancies by type and years since diagnosis

Mortality risk due to renal diseases overtime postdiagnosis
The SMRs reportedly increased with time from diagnosis among the survivors suffering from hematological malignancies overall (Table 2), and were found to be the highest 10 years after the initial diagnosis (SMR = 8.39; 95% CI, 7.62-9.23).

3.3
Type of hematological malignancies linked to higher mortality rate due to renal diseases Majority of deaths due to renal diseases resulted among patients with non-Hodgkin's lymphomas, MM, and chronic lymphocytic leukemia (CLL) accounting for 84% of the total deaths (Figure 1) Abbreviations: CI, confidence interval; HR, hazard ratio.

DISCUSSION
Earlier studies have shown a higher incidence of renal diseases among patients suffering from hematological malignancies; however, the risk of deaths due to renal diseases among this population has not been explored much. This study first provides evidence that the risk of death due to renal diseases among patients with hematological malignancies is about 3.6 times that of the general US population, and recognized the groups of patients linked to higher mortality risk owing to renal disease.
Several studies have investigated the pathogenesis of renal diseases among patients suffering from hematological malignancies.
Canet et al evidenced that renal diseases among patients suffering from hematological malignancies were caused due to direct druginduced nephrotoxicity as well as the complications of the disease [9].
Hypoperfusion and infection are common complications among patients suffering from hematological malignancies, and could lead to acute tubular necrosis, one of the major reasons for renal diseases among patients [7,13]. In addition, for patients suffering renal diseases postcancer diagnosis, nephrotoxic antibiotics against infection and nephrotoxic chemotherapy drugs against hematological malignancies are known to worsen the renal diseases [14].
Patients with all types of hematological malignancies, especially MM, were found to be at a higher risk of death from renal diseases than the general US population. The incidence of MM has not been recorded to increase significantly of late, although the incidence of renal failure among patients suffering MM has tripled [1,15,16]. The multivariate analysis also indicated that MM patients were at a higher risk of death due to renal diseases than patients with other types of hematological malignancies. Monoclonal light chain proteins were the major cause of nephropathy among MM patients, which had toxic effects on glomeruli and tubules, and renal damage in MM most often was found to be tubular nephropathy [9,[17][18][19]. Dehydration, hypercalcemia, sepsis, and nephrotoxic drugs have also been demonstrated to lead to the progression of renal diseases among MM patients [20][21][22]. In addition, CML patients exhibited a significantly high mortality rate due to renal diseases. This is attributable to the development of supportive care and chemotherapy such as tyrosine kinase inhibitors, which aid in prolonging the survival time of such patients [23,24]; therefore, patients were more likely to die due to renal diseases.
Once diagnosed, the risk of death due to renal diseases was found to increase overall among patients suffering from hematological malignancies. This was perhaps due to the longer survival time that led to greater use of the nephrotoxic drugs by patients, which in turn subjected them to a higher risk of death due to renal diseases [1]. Furthermore, a higher age has also been shown to quicken the progression of renal diseases among these cancer survivors [25]. Noteworthy is the first year of cancer diagnosis that represented a greater risk of death due to renal diseases for the majority of hematological malignancies except all the rest. This perhaps is caused by the aggressive treatment imparted immediately following the cancer diagnosis.
The risk of patients suffering from hematological malignancies dying due to renal diseases raised with age at diagnosis, although SMR was found to decrease steadily. This may be due to the higher risk of death from cancer than that from renal diseases for elderly patients with hematological malignancies; therefore, most elderly patients had died due to hematological malignancies prior to dying from renal diseases. This multivariate analysis evidences that Blacks are at a higher risk of death due to renal diseases, which may be linked to the difference between the treatment options opted in distinct races. The differences in the risk of death due to renal diseases between different races are attributable to the economic status, medical level, and genetic factors, whereas the specific mechanism is yet to be studied further.
Our study has several limitations, most of which are related to the SEER database. First, the database is deficient of accurate data regarding chemoradiotherapy, which renders it difficult to assess the influence of chemoradiotherapy on the prognosis of cancer patients.
Second, the reasons for death documented as "Nephritis, Nephrotic Syndrome, and Nephrosis" comprised glomerular diseases, renal failure, other kidney disorders, and ureter. Accurate evaluation of whether the patient died from renal diseases or ureteral diseases could not be made. Third, due to a short follow-up period, the risk of death due to renal diseases among patients diagnosed with hematological malignancies in recent decades was seriously miscalculated.
In spite of these limitations, this study is the first large sample-and population-based study on the risk of death due to renal diseases in patients suffering hematological malignancies. Hence, the results of this study are considered to be reliable and applicable to the rest of the population.
In conclusion, our results indicated that all patients with hematological malignancies are at an increased risk of death due to renal diseases,