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# Impact of early versus conventional kidney replacement therapy initiation in tumor lysis syndrome: a target trial emulation

Justine Serre¹, Guillaume Mulier², Charlotte Boud'hors³, Marie Lemerle⁴, Moustafa Abdel-Nabey¹, Corentin Orvain⁵,⁶,⁷, Anis Chaba¹, Lucie Biard², Julien Demiselle⁸,⁹† and Lara Zafrani¹,¹⁰† ID

**Abstract**

**Background** In the context of tumor lysis syndrome (TLS), the optimal timing and criteria for initiating kidney replacement therapy (KRT) remain unclear. This study aims to assess the effect of initiating KRT at various phosphatemia thresholds on Major Adverse Kidney Events at day 30 (MAKE30).

**Methods and results** We retrospectively emulated a pragmatic clinical trial comparing the effect of KRT initiation at various phosphatemia thresholds versus a conventional approach during TLS on MAKE30. All consecutive patients admitted to the ICU at Saint-Louis University hospital in Paris and Angers University hospital between January 2007 and June 2020, presenting with laboratory TLS were included. The design criteria of a clinical trial were mimicked by using the cloning, censoring and weighting method. The primary outcome was the MAKE30 composite outcome, considering only KRT requirement between day 7 and day 30 for the dialysis criteria. We evaluated multiple phosphatemia thresholds to guide KRT initiation, ranging from 6.20 mg.dL⁻¹ to 9.30 mg.dL⁻¹. Among the initial population of 220 patients, 192 were included in the emulated trial (median age 60 years old, with non-Hodgkin Lymphoma and Acute Leukemia being the most frequent hematological malignancies). TLS-related AKI occurred in 140 patients, and 75 patients met the criteria for MAKE30. Regardless of the phosphate threshold considered, KRT initiation based on phosphate level was not associated with a significant difference in the MAKE30 rate. KRT requirement during the first 7 days (Odd Ratio [OR] 4.01 [1.65–4.86], *p* = 0.003) and non-renal SOFA (OR 1.39 per 1 point increment [1.25–1.57], *p* < 0.001) were identified as factors associated with MAKE30 (multivariable analysis).

**Conclusion** Our results do not support the strategy of KRT initiation based on a sole critical phosphatemia level in TLS patients.

**Keywords** Tumor lysis syndrome, Acute kidney injury, Kidney replacement therapy

Full list of author information is available at the end of the article

<figure><img src="image_2.png" /></figure>

<footnote>†Julien Demiselle and Lara Zafrani participated equally to the study.</footnote>

<footnote>*Correspondence:
Lara Zafrani
lara.zafrani@aphp.fr</footnote>
**Introduction**

Tumor lysis syndrome (TLS) is a consequence of massive malignant cell destruction resulting in the release of large amounts of intracellular components into the systemic circulation. TLS is a life threatening complication occurring mostly in patients with hematological malignancies but can also occur in patients with solid tumors [1]. Laboratory TLS is defined by the presence of at least two of the following biological criteria: an elevation of uric acid, potassium levels or phosphate levels, or a reduction in calcium levels just before or within 7 days after chemotherapy [2]. Clinical TLS is defined by the onset of acute kidney injury (AKI), cardiac dysrhythmias or seizures [2]. In the context of TLS, the presence of AKI is associated with a poor prognosis, characterized by a lower rate of remission of the underlying malignancy [3] and an increased risk of mortality [4]. The pathophysiology of AKI is multifaceted and has yet incompletely been understood. To date, the predominant hypothesis is a crystal-induced nephropathy by calcium phosphate [5, 6], uric acid and xanthine precipitation in kidney tubules. Other recent studies have shown a pathogenic role of renal endothelial lesions induced by histone release during TLS [7]. The primary management approach for TLS involves extensive hydration with physiological saline and the administration of hypouricemic agents [8]. The role of kidney replacement therapy (KRT) in the context of TLS remains unclear and lacks well-defined parameters. Consensus on the criteria for initiating KRT includes situations of impending hyperkalaemia, prolonged oligoanuria, and fluid overload [9, 10]. There is ongoing debate on the potential advantages of early KRT initiation, with the goal of removing harmful intracellular compounds, especially for hyperphosphatemia, before crystal formation or endothelial injury [10]. As data focusing on KRT during TLS primarily comprises case series, further investigation is necessary.

Several clinical trials have investigated the optimal timing for initiating KRT in AKI [11–13]. However, it's noteworthy that these studies excluded patients with TLS. To the best of our knowledge, there has been no exploration of the potential benefits of KRT specifically in the context of TLS. Additionally, no established cutoff for phosphatemia has been proposed to guide the initiation of KRT in TLS patients.

Ideally, addressing this question would require investigation through a prospective controlled trial. However, given the rarity of TLS, the feasibility of conducting such a trial is unlikely. Therefore, we adopted an innovative approach, namely to analyze the potential benefits of KRT initiated based on phosphatemia in patients with TLS, utilizing observational data in an emulated trial analysis.

**Methods**

This retrospective multicenter cohort study was led in two university hospital Intensive care unit (ICU).

**Population**

We included consecutive patients admitted to the ICU at Saint-Louis University hospital in Paris and Angers University hospital (France), between January 2007 and June 2020, all presenting with laboratory TLS. Patients were admitted to the ICU either from outside the hospital or transferred from hematology wards. In both institutions, senior hematologists and intensivists are available around the clock, seven days a week, collaboratively managing high-risk hematological patients. The ICU admission policies remained constant throughout the study period.

**Data collection**

Patient characteristics, such as age, sex and medical history were extracted from medical records. Information pertaining to hematologic malignancy included details on the type of hematologic malignancy, treatments administered, and survival outcomes. Baseline creatinine levels, AKI KDIGO stage, initiation and duration of KRT in the ICU and kidney function recovery after discharge were collected. Biological data available for the patients were extracted from electronic medical records specifically including creatinine levels, urea, potassium levels, calcium levels, phosphatemia levels and lactate dehydrogenase (LDH). Blood tests were conducted every 6 h during ICU hospitalization.

**Definitions**

Laboratory and clinical TLS were defined according to Cairo & Bishop criteria [2]. AKI was defined by an increase in serum creatinine and/or a decreased urine output according to KDIGO 2012 recommendations within 7 days after TLS diagnosis [14]. The classification of AKI stage was established prior to the initiation of the first KRT to prevent potential overclassification for patients undergoing dialysis for TLS without meeting the conventional criteria for KRT. The decision for KRT initiation, categorized as either “conventional approach” or “TLS specific” was determined by the attending clinician. In cases where relevant information was absent from the medical report, this categorization was made retrospectively. KRT initiation was considered “conventional” when one or more of the following severe laboratory abnormalities was observed: hyperkalaemia (K > 6 mEq.L-1), pH below 7.15 related to metabolic acidosis, or acute pulmonary edema due to fluid overload responsible for severe hypoxemia [11] [15]. The risks associated with severe hyperkalaemia, metabolic acidosis, and fluid overload unresponsive to diuretics are well-established and justify timely KRT initiation.
Glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation [16]. Baseline creatinine was considered in a time period of a maximum 1 year and a minimum of 7 days before TLS diagnosis. When baseline creatinine levels were unavailable and no pre-existing kidney disease was documented, an eGFR of 75 ml/min/1.73 m² was arbitrarily assigned, as recommended [17, 18]. Major adverse kidney events within 30 days (MAKE30) is a composite outcome of death, initiation of new KRT, and a decline in kidney function, defined as a 200% increase from basal serum creatinine. This assessment is performed 30 days after the diagnosis of TLS [19, 20]. Given that KRT might be employed exclusively for TLS treatment without typical AKI indications during the acute phase of TLS, our criteria for MAKE30's KRT component focused on KRT instances occurring between day 7 and day 30 after TLS diagnosis. Vital status at 30 days was available for all the patients except for four cases without follow-up information after ICU discharge.

## TLS management

TLS management involved hematologists, nephrologists and intensive care physicians adhering to the guidelines outlined by Jones et al. [9]. Hydration and hypouricemic drugs were administered according to recommended practices. Treatment encompassed hydration with an approximate infusion of 3000 ml/day of saline, aiming to maintain a urine output of 100 ml/m²/h. The hydration prescription was adapted every 6 h based on clinical assessment. Rasburicase was administered at a dose of 0.2 mg/kg/day for a duration of 3 to 7 days, with the reinfusion rate adapted to uric acid levels. Allopurinol was administered to patients with suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency. Given the absence of data on the specific indication and timing of KRT in the context of TLS, the decision to initiate and determine modalities of KRT was at the discretion of the attending physician.

## Study design and patient selection

This observational study emulated a pragmatic clinical trial comparing the effect of KRT initiation timing during TLS on MAKE30, either based on phosphatemia thresholds versus a conventional approach. We constructed a retrospective cohort using medical records of Saint-Louis hospital and Angers hospital. Our analysis included consecutive patients who met the following criteria during the study period: biological or clinical TLS, hospitalized in ICU, without indication of KRT at baseline as per the conventional approach and at least one available phosphatemia before KRT initiation. We defined baseline as the first biological sample of phosphatemia as the date of TLS diagnosis.

Supplementary file 1 outlines the protocol of such a trial.

Explicit emulation of a trial, and in particular aligning the start of follow-up with the assignment of treatment strategies, eliminates immortal time bias, selection/ survivor bias, and lead time bias, which can significantly affect observational studies. This approach is widely adopted in the ICU and nephrology settings and is a strong methodological option, particularly for studying the timing of KRT initiation, when a randomized trial is not feasible [21, 22].

## Treatment strategies

The question was whether the initiation of KRT based on a phosphatemia threshold was superior to the "conventional approach" to improve kidney-related morbidity and survival. Using this approach, we evaluated a range of phosphatemia thresholds to guide the timing of KRT initiation: thresholds investigated ranged from 6.20 mg.dL⁻¹ to 9.30 mg.dL⁻¹ with equally spaced intervals of 0.31 mg. dL⁻¹ (corresponding to a range from 2.0 mmol.L⁻¹ to 3.0 mmol.L⁻¹ with equally spaced intervals of 0.1 mmol. L⁻¹). Strategies of KRT initiation were defined in the first seven days after TLS as opposed to KRT after 7 days that was a criteria included in the MAKE score.

**Primary outcome** the primary composite outcome was the MAKE at 30 days after TLS diagnosis, as defined above.

## Analytic methods

First, we cloned each patient twice for each threshold of phosphatemia. Given *N* analyzed patients, we therefore obtained a sample size 2 *N* in the emulated controlled clinical trial for each phosphatemia threshold. For each patient, one clone was assigned to the strategy of initiating KRT based on phosphatemia crossing a prespecified threshold and the other clone was assigned to the conventional strategy of KRT initiation. In the phosphatemia strategy, KRT could be initiated up to 24 h after the phosphatemia measurement.

Clones were then censored when they deviated from their assigned strategy. Specifically, in the phosphatemia strategy, patients were censored (i) at the end of their follow-up or at seven days if no KRT had been initiated and the phosphatemia threshold had not been met, (ii) at the time of KRT when KRT had been initiated without the threshold being crossed, or (iii) 24 h after phosphatemia crossed the threshold and no KRT had been initiated. In the conventional strategy, patients were censored (i) at the end of their follow-up or at seven days if no KRT had been initiated and the KRT criteria not met, (ii) at the time of KRT when the phosphatemia threshold was crossed less than 24 h before KRT initiation. As a result,
all patients are initially in both groups and they are cen-
sured during follow-up according the aforementioned
rules. We used inverse probability of censoring weighting
with probability of censoring estimated by Cox regres-
sion, to account for informative censoring introduced
by this cloning step. More information on the censoring
models are displayed in supplementary file 2, figures S1
and S2. We used stabilized weights truncated at 1st and
99th percentiles to avoid over-influent weights. Lastly, for
each candidate phosphatemia threshold, the association
between KRT strategy (phosphatemia vs. conventional)
and MAKE30 was assessed by hazards ratios estimated
by weighted Cox regression with robust variance.

Sensitivity analyses were performed with untruncated
weights, and by adding interaction terms in the censoring
model.

As a secondary analysis, we studied the association
between MAKE30 and KRT requirement as per the
conventional strategy in the seven days following the
TLS diagnosis. Multivariable logistic regression was fit-
ted adjusted on clinically relevant explanatory variables.
Analyses were performed on the complete cases sample.

All tests were two-sided and *p*-values lower than 0.05
were considered significant. Analyses were performed on
R platform, version 4.3.0.

Results

Among 240 eligible patients, 220 were included, with 192
of them participating in the emulated trial (see Fig. 1 for
flowchart and reasons for exclusion). Of the 18 patients
meeting “conventional” RRT criteria and thus excluded
from the cohort for the purpose of the present analysis,

<figure><img src="image_3.png" /><figcaption>**Fig. 1** Flowchart of the emulated trial approach. The *n* = 192 patients in the analyzed set were cloned 1:1 in silico to obtain a 1:1 controlled sample. In the emulated intervention group, a sequence of phosphatemia values ranging from 6.20 to 9.30 mg/dL were evaluated to define the KRT decision threshold. For illustration purposes and legibility, the distribution of MAKE30 events per emulated group is reported for 3 phosphatemia thresholds (minimum, maximum and intermediate). KRT: Kidney replacement Therapy, MAKE: Major Adverse Kidney event</figcaption></figure>
the majority (n = 11, 61%) required KRT due to hyperkalaemia, while 4 patients (22%) required KRT for pulmonary overload associated with prolonged oliguria (> 72 h) and 3 (17%) for metabolic acidosis (pH < 7.15). Baseline characteristics of participants, including biological parameters at ICU admission, are presented in Table 1, according to KRT requirement.

Patients were predominantly men, with a median age of 60 years old. Non-Hodgkin lymphoma and acute leukemia accounted for more than 90% of the underlying hematological malignancies causing TLS. Clinical TLS occurred in 140 patients, with kidney involvement being the main contributor, while neurological and hemodynamic involvement occurred in one and four patients respectively. Among the 140 (63.6%) patients with TLS-related AKI, 48 patients (21.8%) met the criteria for stage 3 of the KDIGO definition. Of note, chronic kidney disease was rare in our population.

Characteristics of TLS management and main outcomes are reported in Table 2.

The primary outcome was available in 217 patients. Seventy-five patients fulfilled criteria for MAKE30.

Next, using an emulated trial with the above-defined method of cloning, censoring and weighting, we assessed whether a strategy of initiation of KRT according to various phosphatemia thresholds, compared to a conventional strategy, affected the main outcome in the 192 patients with available data for the models.

As presented in Fig. 2, whatever the chosen phosphate threshold, the phosphatemia strategy for KRT initiation was not associated with a significant difference in MAKE30 as compared to the conventional approach. Kaplan Meier curves for three different values of phosphate threshold (Fig. 3) are reported to illustrate this finding, which was confirmed in sensitivity analysis (see Supplementary file 3, Figures S3, S4, S5).

Finally, to evaluate factors associated with MAKE-30, we performed univariate and multivariable analysis (Supplemental Tables 1 and Table 3, respectively). In multivariable analysis, KRT requirement during the first 7 days

<table><caption>**Table 1** Baseline characteristics of patients according to KRT initiation</caption><thead><tr><th></th><th>All population<br>(n = 220)</th><th>No KRT<br>(n = 90)</th><th>KRT<br>(n = 130)</th></tr></thead><tbody><tr><td><strong>Baseline characteristics</strong></td><td></td><td></td><td></td></tr><tr><td>Gender (F), n (%)</td><td>66 (30.0)</td><td>35 (38.9)</td><td>31 (23.8)</td></tr><tr><td>Age (Years), Med [IQR]</td><td>60 [48–69]</td><td>59 [45–69]</td><td>60 [50–68]</td></tr><tr><td>Baseline serum creatinine (mg.dL<sup>-1</sup>), Med [IQR]</td><td>0.90 [0.76–1.03]</td><td>0.85 [0.75–1.01]</td><td>0.92 [0.78–1.03]</td></tr><tr><td>SOFA score, Med [IQR]</td><td>6 [3–9]</td><td>5 [3–7]</td><td>6 [3–9]</td></tr><tr><td>Modified SOFA score, Med [IQR]</td><td>4 [2–6]</td><td>4 [2–7]</td><td>4 [1–6]</td></tr><tr><td><strong>Underlying comorbidities</strong></td><td></td><td></td><td></td></tr><tr><td>Hypertension, n (%)</td><td>63 (28.6)</td><td>23 (25.6)</td><td>40 (30.8)</td></tr><tr><td>Diabetes mellitus, n (%)</td><td>29 (13.2)</td><td>10 (11.1)</td><td>8 (14.3)</td></tr><tr><td>Chronic heart failure, n (%)</td><td>15 (6.9)</td><td>6 (6.8)</td><td>9 (6.9)</td></tr><tr><td>HIV positive, n (%)</td><td>29 (13.2)</td><td>7 (7.8)</td><td>22 (16.9)</td></tr><tr><td>Chronic Kidney Disease, n (%)</td><td>13 (5.9)</td><td>4 (4.4)</td><td>9 (6.9)</td></tr><tr><td><strong>Underlying malignancies</strong></td><td></td><td></td><td></td></tr><tr><td>Acute Leukemia, n (%)</td><td>70 (31.8)</td><td>36 (40.0)</td><td>34 (26.2)</td></tr><tr><td>Non-Hodgkin lymphoma, n (%)</td><td>139 (63.2)</td><td>49 (54.4)</td><td>90 (69.2)</td></tr><tr><td>Multiple Myeloma, n (%)</td><td>3 (1.4)</td><td>2 (2.2)</td><td>1 (0.8)</td></tr><tr><td>Solid tumor, n (%)</td><td>3 (1.4)</td><td>2 (2.2)</td><td>1 (0.8)</td></tr><tr><td>Others, n (%)</td><td>5 (2.3)</td><td>1 (1.1)</td><td>4 (3.1)</td></tr><tr><td><strong>Risk factors for AKI</strong></td><td></td><td></td><td></td></tr><tr><td>Nephrotoxic agents, n (%)</td><td>78 (35.5)</td><td>25 (27.8)</td><td>53 (40.8)</td></tr><tr><td><strong>TLS biochemical parameters at admission</strong></td><td></td><td></td><td></td></tr><tr><td>Phosphate (mg.dL<sup>-1</sup>), Med [IQR]</td><td>4.37 [3.41–5.80]</td><td>4.28 [3.35–5.22]</td><td>4.65 [3.41–6.20]</td></tr><tr><td>Uric Acid (mg.dL<sup>-1</sup>), Med [IQR]</td><td>8.74 [5.63–12.36]</td><td>8.62 [5.74–11.61]</td><td>8.89 [5.62–13.10]</td></tr><tr><td>Potassium (mmol.L<sup>-1</sup>), Med [IQR]</td><td>4.3 [3.9–4.8]</td><td>4.2 [3.6–4.6]</td><td>4.6 [4.1–5.0]</td></tr><tr><td>Calcium (mg.dL<sup>-1</sup>), Med [IQR]</td><td>8.80 [8.00–9.60]</td><td>8.80 [8.00–9.60]</td><td>8.80 [8.00–9.60]</td></tr><tr><td>LDH (UI/L), Med [IQR]</td><td>2403 [1150–5082]</td><td>2318 [1157–5125]</td><td>2494 [1186–4798]</td></tr><tr><td>Serum creatinine (mg.dL<sup>-1</sup>) Med [IQR]</td><td>1.38 [0.96–2.17]</td><td>1.12 [0.83–1.68]</td><td>1.60 [1.12–2.70]</td></tr><tr><td><strong>Disseminated Intravascular Coagulation, n (%)</strong></td><td>48 (21.8)</td><td>22 (24.4)</td><td>26 (20.0)</td></tr></tbody></table>

Data are presented as counts and percentages for categorical data and as median (Med) with interquartile range (IQR) for quantitative data

AKI: Acute Kidney Injury, HIV: Human Immunodeficiency Virus, LDH: Lactate DeHydrogenase, SOFA: Sequential Organ Failure Assessment, Modified SOFA: SOFA without kidney component, TLS: tumor lysis syndrome, KRT: Kidney Replacement Therapy
<table><caption>**Table 2** Tumor lysis management and main outcomes according to KRT initiation</caption><thead><tr><th></th><th>All population<br>(n = 220)</th><th>No KRT<br>(n = 90)</th><th>KRT<br>(n = 130)</th></tr></thead><tbody><tr><td><strong>Treatment of TLS</strong></td><td></td><td></td><td></td></tr><tr><td>Allopurinol, n (%)$</td><td>77/217 (35.5)</td><td>32/89 (36.0)</td><td>45/128 (35.2)</td></tr><tr><td>Rasburicase, n (%)*</td><td>155/219 (70.8)</td><td>69 (76.7)</td><td>86/129 (66.7)</td></tr><tr><td><strong>TLS outcome</strong></td><td></td><td></td><td></td></tr><tr><td>MAKE30, n (%)$</td><td>75/217 (34.6)</td><td>20/88 (22.7)</td><td>55/129 (42.6)</td></tr><tr><td>- Mortality criteria, n (%)$</td><td>61/217 (28.1)</td><td>19/88 (21.6)</td><td>42/129 (32.6)</td></tr><tr><td>- Kidney Replacement Therapy criteria, n (%)$</td><td>19/217 (8.8)</td><td>-</td><td>19/129 (14.7)</td></tr><tr><td>- Serum creatinine criteria, n (%)$</td><td>8/217 (3.7)</td><td>1/88 (1.1)</td><td>7/129 (5.4)</td></tr><tr><td>AKI, n (%)</td><td>140 (63.6)</td><td>31 (34.4)</td><td>109 (83.8)</td></tr><tr><td>- KDIGO 1, n (%)</td><td>52 (23.6)</td><td>18 (20.0)</td><td>34 (26.2)</td></tr><tr><td>- KDIGO 2, n (%)</td><td>40 (18.2)</td><td>8 (8.9)</td><td>32 (24.6)</td></tr><tr><td>- KDIGO 3, n (%)</td><td>48 (21.8)</td><td>5 (5.6)</td><td>43 (33.1)</td></tr></tbody></table>

Data are presented as counts and percentages for categorical data

$ information was unavailable in 3 patients, * information was unavailable in 1 patients, AKI: Acute Kidney Injury, KDIGO: Kidney Disease Improving Global Outcomes, MAKE30: Major Adverse Kidney Events at day 30, TLS: Tumor Lysis Syndrome. KRT: Kidney Replacement Therapy

<figure><img src="image_4.png" /><figcaption>**Fig. 2** Results from principal analysis on MAKE score relative to the threshold of phosphatemia with truncated stabilized weights. It depicts the hazard ratio (strategy KRT vs. no KRT when phosphatemia exceeds the threshold) estimated by weighted Cox regression. KRT: Kidney replacement Therapy, MAKE: Major Adverse Kidney event</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Fig. 3** Weighted Kaplan-Meier curves of the MAKE30-free survival since first phosphate sampling according to KRT-decision group, using the emulated trial datasets. In the emulated intervention group, a sequence of phosphatemia values ranging from 6.20 to 9.30 mg/dL were evaluated to define the KRT decision threshold; for illustration purposes and legibility, the MAKE30-free survival by emulated group is reported for 3 phosphatemia thresholds only, across this range (minimum, maximum and intermediate)</figcaption></figure>

<table><caption>**Table 3** Multivariable analysis of factors associated with MAKE30</caption><thead><tr><td>Variable</td><td>OR</td><td>P value</td></tr></thead><tbody><tr><td>No KRT at day 7</td><td>1 (Reference)</td><td></td></tr><tr><td>KRT during the first 7 days</td><td>4.01 [1.65;4.86]</td><td>0.003</td></tr><tr><td>Non Hodgkin lymphoma</td><td>1 (Reference)</td><td></td></tr><tr><td>Acute leukemia</td><td>1.19 [0.52;2.69]</td><td>0.682</td></tr><tr><td>Other</td><td>2.08 [0.47;9.75]</td><td>0.337</td></tr><tr><td>Non renal SOFA (by 1 point-increment)</td><td>1.39 [1.25;1.57]</td><td>&lt; 0.001</td></tr><tr><td>LDH at admission (by 1000 UI/L increment)</td><td>0.99 [0.91;1.08]</td><td>0.884</td></tr><tr><td>Clinical tumor lysis syndrome</td><td>1.79 [0.72;4.65]</td><td>0.219</td></tr></tbody></table>

KRT: Kidney replacement therapy, LDH: Lactate DeHydrogenase, SOFA: Sequential Organ Failure Assessment

(Odd Ratio [OR] 4.01 [1.65–4.86], *p* = 0.003) and non-renal SOFA (OR 1.39 per 1 point increment [1.25–1.57], *p* < 0.001) were independently associated with MAKE30.

Among patients requiring KRT, dialysis catheter-related complications occurred in 7 (5.5%) patients with 3 catheter-related bloodstream infections and 4 cases of

catheter-related bleeding at the puncture site requiring red blood cell transfusion.

## Discussion

In this study, we investigated the effectiveness of a pre-emptive KRT strategy based on phosphate levels during TLS with regard to a composite outcome encompassing
kidney recovery and mortality. Despite testing vari-
ous phosphate thresholds, an early KRT initiation strat-
egy based on phosphatemia was not associated with
improved patient's outcomes.

There is a lack of studies addressing the indications and
optimal timing of KRT during TLS. Guidelines by Jones
et al. [9] recommend KRT for TLS patients exhibiting
intractable fluid overload, hyperkalaemia, hyperuricemia,
hyperphosphatemia, or hypocalcemia. If KRT is excep-
tionally required in the rasburicase era for hyperurice-
mia, fluid overload and hyperkalaemia remained classical
emergency situations. Hyperphosphatemia as a sole crite-
ria for beginning KRT remains a matter of debate. Hyper-
phosphatemia is an early marker for AKI in the setting
of TLS [23], and some propose a phosphatemia thresh-
old of 2 mmol/L to initiate KRT, even in the absence of
AKI [10]. Prophylactic use of KRT (using a combination
of Continuous Venovenous Hemofiltration (CVVH) with
prephase chemotherapy) has also been proposed by some
expert teams in adults and children, for patients with
spontaneous TLS or at high risk of developing TLS [24,
25]. However, these suggestions are based on retrospec-
tive analyses of a small number of patients, precluding
any firm conclusions regarding the efficacy and safety of
this strategy and the optimal timing for initiating KRT in
TLS-induced AKI remains uncertain [9]. Hence, the low
level of recommendation on KRT indications and timing
during TLS mirrors the absence of available randomized
studies.

Importantly, existing evidence from general ICU set-
tings indicates no benefit from early KRT during AKI.
Three published large multicenter randomized control
studies that compared early and delayed strategies of
KRT [11, 13, 26] in critically ill patients did not found any
benefit of an early strategy when compared to a delayed
strategy, in terms of mortality. However, patients with
TLS have been excluded from these studies [11].

In contrast to the broader ICU context, TLS presents
a unique scenario where KRT has been suggested as an
effective strategy to mitigate kidney structural damage
caused by the release of high phosphorus levels from
malignant cells. The levels of phosphorus in malignant
cells can be up to four times higher than those found in
normal cells. The swift release of these stores can lead
to hyperphosphatemia, precipitating with calcium into
the kidney tubules. This process induces calcium phos-
phate nephropathy, subsequently causing AKI, which
further exacerbates hyperphosphatemia, thus creating a
vicious cycle [5, 27]. Many physicians facing TLS com-
mence KRT well before the development of any conven-
tional indications for KRT. However, despite the plausible
pathophysiological rationale, there is a lack of clinical
evidence supporting the preemptive use of KRT in TLS.

The challenges associated with conducting a random-
ized study on KRT initiation during TLS are manifold
due to the rarity of the disease, requiring close coordi-
nation among hematologists, oncologists, nephrologists,
and intensivists. Additionally, logistical constraints, such
as the need for central venous catheter insertion and
ICU availability, further complicate such endeavors. Fur-
thermore, retrospective studies face inherent difficulties
in interpreting the timing of dialysis initiation, includ-
ing concerns about immortal time, selection/survivor
biases, and lead time biases. Our study design, incorpo-
rating cloning, censoring, and weighting, aims to miti-
gate these biases by emulating a target trial and aligning
eligibility and treatment strategies at baseline [21]. Such
an approach ensures to take into account time-varying
confounders and immortal-time bias [28], and appears
relevant in the setting of clinical research in the field of
intensive care and nephrology research, allowing us to
test our hypothesis for various phosphatemia thresholds
for the timing of KRT.

However, this statistical approach suffers from limita-
tions: it is an observational study, as opposed to a pro-
spective controlled assessment in a randomized trial.
Due to the observational design, we could only adjust for
measured confounders. Thus, there may still be unmea-
sured confounding factors that could bias the results,
such as confounding by indication, meaning unmeasured
factors associated with patient's risk in relation to KRT
initiation. Moreover, we could not perform the emulated
trial analysis using thresholds outside the range of 6.20
mg.dL⁻¹ to 9.30 mg.dL⁻¹ as more extreme thresholds
were directly linked to KRT status with little to no vari-
ability (e.g. above 9.30 mg.dL⁻¹ nearly all patients had
KRT).

Furthermore, the study involved patients from two
specialized centers, with high expertise in the care of
patients at high risk of TLS (hydration management,
early rasburicase use for example), and, consequently,
whether our findings can be generalized to other settings
remain uncertain.

Two potential interpretations arise from our study
findings:

Firstly, early KRT might not confer benefits in TLS
patients. KRT might be ineffective in protecting the kid-
ney from the release of harmful components by malig-
nant cells during TLS. Moreover, the introduction of early
KRT could potentially result in adverse effects, notably
catheter-related complications, as illustrated in this work,
especially in thrombocytopenic and immunosuppressed
patients. Furthermore, KRT in cancer patients may be
associated with modifications in the effectively received
doses of chemotherapy regimens, potentially dampening
the anti-tumoral effect of the drug, reducing the likeli-
hood of achieving complete remission of the underlying
malignancy. This is due to the fact that the pharmacokinetics of chemotherapeutic drugs in high-grade hematological malignancies in patients undergoing KRT are not well known.

Secondly, phosphate may not be an ideal marker for guiding KRT strategies in TLS, as other mechanisms, such as crystal-independent pathways involving extracellular histones, damage-associated molecular patterns, and pro-inflammatory cytokines, could contribute to AKI in TLS [29, 30]. Indeed, if AKI can be due to crystal dependent mechanisms during TLS, including calcium-phosphate nephropathy, Arnaud et al. showed that calcium-phosphate crystals are exceptional in TLS patients, since the guidelines do not recommend urine alkalinization. Moreover, they showed that TLS patients release huge amounts of extracellular histones into the circulation that may exert cytotoxic effects on kidney endothelial cells [30].

Another challenge in managing patients with TLS involves selecting the appropriate KRT modality—intermittent versus continuous. Some authors predominantly advocate for CVVH in TLS cases [25, 31, 32], while others favor daily intermittent hemodialysis [33]. Considering the continuous release of intracellular content from lysing tumor cells, continuous modalities are sometimes favored over intermittent hemodialysis to mitigate the risk of “rebound” hyperkalaemia or hyperphosphatemia. On the other hand, conventional hemodialysis demonstrates a more effective clearance of potassium and chemotherapy can be administered between two sessions, mitigating the risk of underdosing the treatment. In our study, we reported a consistent strategy with hemodialysis as the first modality of KRT in a large majority of included patients, which precluded us from drawing any firm conclusions about the best modality to use in TLS patients.

In conclusion, our results do not support the strategy of KRT initiation based on a sole critical phosphatemia level in TLS patients. Whether due to potential deleterious effects of early KRT or the inadequacy of serum phosphate as a relevant clinical marker for kidney associated outcomes in this setting, further investigations are warranted to refine KRT strategies in TLS.

**Abbreviations**

<table><tr><td>TLS</td><td>Tumor lysis syndrome</td></tr><tr><td>AKI</td><td>Acute kidney injury</td></tr><tr><td>ICU</td><td>Intensive care unit</td></tr><tr><td>KRT</td><td>kidney replacement therapy</td></tr><tr><td>GFR</td><td>Glomerular filtration rate</td></tr><tr><td>MAKE30</td><td>Major adverse kidney events within 30 days</td></tr><tr><td>G6PD</td><td>glucose-6-phosphate dehydrogenase</td></tr><tr><td>CVVH</td><td>Continuous venovenous hemofiltration</td></tr><tr><td>SOFA</td><td>Sequential organ failure assessment</td></tr></table>

**Supplementary Information**

The online version contains supplementary material available at https://doi.org/10.1186/s13613-025-01439-x.

Supplementary Material 1

Supplementary Material 2

Supplementary Material 3

**Acknowledgements**

Not applicable.

**Author contributions**

J.D, J.S and L.Z designed the study, performed data management and wrote the paper; L.B. and G.M. did the statistical analysis. C.B, M.L, A.C, M.AN and C.O provided substantial contribution to the acquisition of data.

**Funding**

None.

**Data Availability**

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

**Declarations**

**Ethics approval and consent to participate**

This study was approved by Institutional Review Boards (IRB) ("Comité d'Evaluation de l'Ethique des projets de Recherche Biomédicale Paris Nord"— IRB 00006477—of Paris 7 University and the institutional Ethics Committee of the Angers University Hospital —2018/76). According to the French regulation, written consent was not required for this non interventional study. Patients were informed that their data might be used for research, none refused. The study was conducted following the Declaration of Helsinki principles.

**Competing interests**

LZ reports receiving fees for lectures for MSD and Sanofi. Other authors declare no conflict of interest.

**Author details**

¹Department of Medical Intensive Care, Hôpital Saint-Louis, AP-HP, Paris, France

²Department of Biostatistics and Medical Information, AP-HP, Hôpital Saint-Louis, Université Paris Cité, Paris, France

³Department of Nephrology, Dialysis, Transplantation, CHU Angers, Angers, France

⁴Department of Medical Intensive Care, CHU Angers, Angers, France

⁵Department of Hematology, CHU Angers, Angers, France

⁶Fédération hospitalo-universitaire « Grand Ouest against Leukemia », Nantes, France

⁷Inserm UMR 1307, CNRS UMR 6075, Nantes Université, Université d'Angers, Angers CRCI2NA, France

⁸Department of Medical Intensive Care, Nouvel Hôpital Civil, Strasbourg University Hospital, Strasbourg, France

⁹CRBS (Centre de Recherche en Biomédecine de Strasbourg), FMTS (Fédération de Médecine Translationnelle de Strasbourg), INSERM UMR 1260, Regenerative Nanomedicin, University of Strasbourg, Strasbourg, France

¹⁰INSERM UMR 944, Université Paris Cité, Paris, France

Received: 29 June 2024 / Accepted: 16 January 2025

Published online: 04 April 2025

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