Acute kidney injury following induction of chemotherapy: Diagnosis and management in critical care

Abstract

A 48-year-old gentleman who had recently commenced chemotherapy for diffuse B-cell lymphoma was admitted to hospital with nausea and generalised weakness. He developed abdominal pain and oliguric acute kidney injury with multiple electrolyte derangements and was transferred to the intensive care unit (ICU). His condition deteriorated, requiring endotracheal intubation and renal replacement therapy (RRT). Tumour lysis syndrome (TLS) is a common and life-threatening complication of chemotherapy and represents an oncological emergency. TLS affects multiple organ systems and is best managed in the ICU with closer monitoring of fluid balance, serum electrolytes, cardiorespiratory and renal function. TLS patients may go on to require mechanical ventilation and RRT. TLS patients require input from a large multidisciplinary team of clinicians and allied health professionals.

Keywords

Critical care haematology oncology tumour lysis syndrome renal replacement therapy hyperkalaemia electrolyte disturbance

Case presentation

A 48-year-old gentleman was admitted to hospital with nausea and generalised weakness. He had recently been diagnosed with stage IV diffuse B-cell lymphoma and commenced induction chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) the previous day.

Initial vital signs were relatively normal, with only a mild tachycardia. On examination, the gentleman was dehydrated with bilateral flank pain; his chest sounded clear. He was admitted to the haematology ward for close monitoring and fluid replacement.

His admission blood tests showed a significant AKI with multiple electrolyte abnormalities (Table 1 below). By the evening he had become tachypnoeic with a respiratory rate of 24, and an increasing oxygen requirement of 40%. He was also hypotensive (94/50) and anuric despite having received 2 L of intravenous crystalloid solution. Due to the increasing oxygen requirement, hypotension and anuric AKI, a decision was made to transfer him to the intensive care unit (ICU) for closer monitoring and organ support if required.

Table 1.

Blood results taken on admission to hospital, demonstrating stage 2 acute kidney injury with hyperphosphataemia, hyperkalaemia, hypocalcaemia, and high uric acid.

Blood test results on admission
Blood marker	Result (normal range)
Creatinine	190 μmol/L (50–120 μmol/L)
Urea	20 mmol/L (2.5–7.0 mmol/L)
Potassium	6.1 mmol/L (3.5–5.0 mmol/L)
Phosphate	3.10 μmol/L (0.74–1.40 μmol/L)
Corrected calcium	2.01 mmol/L (2.20–2.60 mmol/L)
Uric acid	600 μmol/L (200–430 μmol/L)

Management and treatment

The patient had already received intravenous rasburicase and allopurinol prior to admission. A CT scan of the abdomen and pelvis scan revealed no evidence of obstructive uropathy or renal disease. Central venous access was established, and aggressive intravenous fluid therapy continued. A bolus of intravenous furosemide was also given with the aim of generating a urine output of ∼180 mL/hour. By this time, his respiratory effort had significantly with an oxygen requirement of 80%. Chest X-ray demonstrated pulmonary congestion.

He was then intubated and ventilated due to respiratory distress, and a noradrenaline infusion was started due to hypotension following induction of anaesthesia. His electrolytes were monitored 2-hourly and did not show significant abnormality. The following morning, his urine output remained poor, and he was demonstrating further signs of volume overload with an increasing fraction of inspired oxygen (FiO2). Due to his persistent metabolic acidosis and fluid overload, it was decided to commence continuous veno-venous haemodiafiltration (CVVHDF) with a target fluid removal of 200 mL/hour. His fluid removal target was maintained but he did require increasing doses of noradrenaline to support his blood pressure.

CVVHDF was continued for 48 h, during which time his blood pressure and urine output improved and the fluid removal via the filter was gradually reduced. This also resulted in decreasing noradrenaline requirements, as well as a decreasing FiO2 and inspiratory pressure support requirement. On day 3 of his ICU admission, he was successfully extubated onto high-flow nasal oxygen and his noradrenaline infusion was weaned off. He was also taken off CVVHDF support and was passing good amounts of urine independently. His renal function and electrolytes had almost returned to baseline. He continued to receive IV rasburicase daily and was discharged back to the haematology ward a day.

Discussion

Tumour lysis syndrome

Tumour Lysis Syndrome (TLS) is a largely metabolic complication following the induction of cancer therapy,¹ which was first reported in 1929.² The incidence of TLS depends on a myriad of factors, such as cancer type, tumour burden, therapy given and pre-existing renal function.³ As a result, the incidence can range greatly from as low as 4%, up to 30% in certain patient groups.^4,5 Haematological malignancies are most associated with TLS, specifically non-Hodgkin lymphoma and acute myeloid leukaemia.⁶

TLS represents an oncological emergency and has an estimated overall in-hospital mortality of 21%.⁷ Thus, it is recommended that these patients are managed in an ICU or specialist haematology centre.^8,9

Pathophysiology

TLS is caused by the massive and sudden breakdown of tumour cells and the consequent leakage of intracellular content (including nucleic acids, phosphorus, and potassium) into the systemic circulation. The kidney normally excretes these components to maintain homeostasis, however during TLS these mechanisms become leading to their accumulation within the blood. Clinical signs and symptoms reflect these underlying metabolic derangements.

Hyperuricaemia

A hallmark of TLS is hyperuricemia which normally develops from 48-72 h following treatment administration.¹⁰ Cancer cells carry a significant burden of nucleic acids due to their increased turnover and their lysis leads to large amounts of purine-containing nucleic acids (adenosine and guanine) being released into the serum. This triggers the purine catabolic pathway, where nucleic acids are first converted to hypoxanthine and xanthine, and subsequently metabolized into uric acid. When the compensatory response of the kidney is exhausted, uric acid crystals can precipitate, thus leading to obstructive uropathy and acute kidney injury.

Hyperphosphataemia

Hyperphosphatemia usually occurs from 24-48 h following treatment administration¹⁰ when the release of intracellular phosphate exceeds the renal excretion threshold. The surplus serum phosphate consequently binds to calcium, resulting in precipitation of calcium phosphate throughout the body and secondary hypocalcaemia. Hypocalcaemia can lead to muscle cramps, tetany, seizures, and life-threatening conditions including cardiac arrhythmia and acute renal failure due to calcium phosphate deposition.

Hyperkalaemia

Hyperkalaemia, an additional consequence of massive tumour lysis, might occur from 6-72 h following treatment administration¹⁰ and is arguable the most critical electrolyte disturbance associated with TLS. Potassium is a highly concentrated intracellular electrolyte and its release into systemic circulation can lead to symptoms such as muscle cramps, diarrhoea, nausea, vomiting, weakness, and paraesthesia. Severe hyperkalaemia can result in fatal ventricular arrhythmias.

Diagnosis

The diagnosis of TLS can be made by recognising clinical and biochemical features. Clinically, TLS is normally seen in a patient with a known cancer diagnosis, who has usually recently commenced treatment within the previous 24–48 h,¹⁰ though it can occur spontaneously. Signs and symptoms of TLS may include fatigue, nausea and vomiting, diarrhoea, irritability, confusion, lower urinary tract symptoms.¹¹

TLS is classified into either laboratory TLS (LTLS) or clinical TLS (CTLS). LTLS is formally diagnosed via the Cairo-Bishop diagnostic criteria, as shown below in Table 2. Two or more of the listed abnormalities in Table 2 are required to be present within 3 days before starting or 7 days after initiation of chemotherapy for a diagnosis of LTLS to be made. CTLS requires the criteria of LTLS to be met as well as the presence of one of the following clinical features: seizure, cardiac arrythmia, acute kidney injury or death.¹²

Table 2.

Cairo-Bishop criteria for the diagnosis of tumour lysis syndrome. Two or more biochemical features must be present to diagnosis LTLS.

Cairo-bishop criteria
Blood marker	Result
Uric acid	>475.8 μmol/L
Phosphate	>1.5 μmol/L
Potassium	>6 mmol/L
Corrected calcium	<1.75 mmol/L

Investigations and monitoring

As TLS is a metabolic condition, the mainstay of investigation is by repeated sampling of blood 4–6 hourly for potassium, uric acid, phosphate, corrected calcium, lactate dehydrogenase and renal function markers.¹³

Furthermore, regular monitoring of blood pH via arterial blood gas sampling and intensive fluid input: output monitoring is required to ensure renal function is adequate and diuresis of metabolites is effective.¹⁴ Thorough fluid status examination should also be regularly undertaken to examine for clinical signs of volume overload.

Cardiac monitoring with regular electrocardiogram (ECG) review should also be instituted to assess for cardiac arrythmias arising secondary to TLS. Similarly, inducing a large volume diuresis may precipitate cardiovascular instability secondary to hypovolaemia and thus invasive blood pressure monitoring should be offered.¹⁵

Monitoring respiratory function and work of breathing is also crucial in the management of patients with TLS. Volume overload secondary to oliguria may cause pulmonary oedema leading to respiratory failure. Alternatively, TLS may ignite a cytokine storm leading to an acute respiratory distress syndrome.¹⁶ In either case, close monitoring is required to allow early institution of CVVHDF or mechanical ventilation.

Management

Risk stratification

The management of TLS largely centres around identifying at risk individuals and focusing on preventing the development of TLS. The British Society for Haematology has identified several risk factors for the development of TLS. These include the presence of high-grade tumours with rapid cell turnover, high tumour burden, renal impairment, use of cell-cycle specific chemotherapeutics and drugs that contribute to hyperuricaemia.¹⁷ The preventative management depends on the level of risk. Table 3 summarises the criteria used to stratify risk in adults.⁶

Table 3.

A table summarising the risk stratification for tumour lysis syndrome in adults.⁶

Risk stratification for tumour lysis syndrome in adults
Low risk	Moderate risk	High risk
Solid tumours, multiple myeloma, chronic myeloid leukaemia, indolent non-hodgkin lymphoma, hodgkin lymphoma, chronic lymphocytic leukaemia	Acute myeloid leukaemia with WBC 25–100 x 109/L	Acute myeloid leukaemia with WBC ≥100 x 109/L
Acute myeloid leukaemia with WBC <25 x 109/L and LDH <2 x upper normal limit	Acute myeloid leukaemia with WBC <25 x 109/L and LDH ≥2 x upper normal limit	Acute lymphoblastic leukaemia with WBC ≥100 x 109/L +/− LDH ≥2 x upper normal limit
Adult intermittent grade non-hodgkin lymphoma and LDH <2 x upper normal limit	Adult intermittent grade non-hodgkin lymphoma and LDH ≥2 x upper normal limit	Burkitt lymphoma stage III/IV +/− LDH ≥2 x upper normal limit
Adult anaplastic large cell lymphoma	Acute lymphoblastic leukaemia with WBC <100 x 109/L and LDH <2 x upper normal limit	Lymphoblastic leukaemia stage III/IV +/− LDH ≥2 x upper normal limit
	Burkitt lymphoma with LDH <2 x upper normal limit	Rare solid tumours or tumours with advanced staging with renal dysfunction
	Lymphoblastic leukaemia stage I/II with LDH <2 x upper normal limit	Rare solid tumours or tumours with advanced staging with hyperuricaemia, hyperkalaemia or hyperphosphataemia

Those deemed to be either low or moderate risk of developing TLS can be managed with intravenous fluid replacement, allopurinol prophylaxis and electrolyte monitoring. Fluid rehydration should be commenced at least 2 days prior to chemotherapy. The levels of LDH, urate, sodium potassium, phosphate and urea should be monitored twice daily for the first 3 days, and thereafter daily to ensure TLS is not developing.¹⁸ Management for those deemed high risk for TLS is largely the same, but with the addition of rasburicase prophylaxis instead of allopurinol.¹⁷

Reducing uric acid levels

Both allopurinol and rasburicase reduce uric acid levels. Allopurinol is a xanthine oxidase inhibitor, acting to prevent conversion of xanthine to urate. However, this allopurinol treatment can cause accumulation of xanthine and hypoxanthine, predisposing individuals to xanthine nephropathy. Consequently, treatment with allopurinol is only recommended for those at low or moderate risk of developing TLS. Rasburicase is a recombinant urate oxidase which converts urate into a more water-soluble product called allantoin.¹⁴ A meta-analysis found that a single dosed regimen of rasburicase produced a greater reduction in uric acid levels compared to allopurinol.¹⁹ A dose of 200–400 mg/day of allopurinol, given over 3 divided doses, should be given for at least 7 days post-chemotherapy. If rasburicase is used, the recommended dose is 0.2 mg/kg and this should be given for 5–7 days post-chemotherapy.¹⁷

Intravenous hydration therapy

In those with confirmed TLS, aggressive rehydration is required to prevent uric acid and calcium phosphate deposition in the renal tubules. Fluid replacement increases renal blood flow and the glomerular filtration rate. This results in diuresis and elimination of urate and phosphate.²⁰ Guidelines suggest that 3 litres of fluid should be given over 24 h. This can be administered as hypotonic or isotonic solutions but must not contain any additional potassium.²¹ The target urine output is 100 mL/hour. If intravenous fluids alone are insufficient to achieve this urine output, loop diuretics may also be used. Loop diuretics should be avoided in patients with obstructive uropathy or those who are clinically hypovolaemic.

Electrolyte correction

Electrolyte levels should be assessed at least 6-hourly. Hyperphosphataemia can be managed with intravenous fluids and using non-calcium oral phosphate binders, such as aluminium hydroxide. Hypocalcaemia often resolves with the treatment of hyperphosphataemia and should not be treated if asymptomatic. Calcium gluconate may be given to those who are symptomatic. Hyperkalaemia should be treated, firstly via medical management, such as intravenous insulin and dextrose infusion and patients should be kept on a cardiac monitor. If there are any ECG abnormalities present, such as prolonged PR intervals, broad QRS complexes or tall T waves, intravenous calcium gluconate should be given.^17,22 Any hypokalaemia should be monitored closely and only replaced if levels are felt to be significantly low.

Renal replacement therapy and organ support

Admission to ICU is often required. The most common reason for this is for renal replacement therapy.²³ This may be needed for correction of refractory hyperkalaemia, hyperphosphataemia, hypocalcaemia, volume overload and any metabolic acidosis secondary to hyperuricaemia.^17,24,25 This can be delivered as CVVHDF or as intermittent haemodialysis. CVVHDF has been shown to be more effective in lowering serum phosphate levels compared to intermittent haemodialysis and seems to be more suitable for critically unwell patients.²⁶ A study conducted in a paediatric population found daytime treatment with CVVHDF resulted in improvement of electrolyte abnormalities much sooner than recovery in renal function.²⁵

In severe cases, patients may develop hypoxic respiratory failure, thus requiring intubation and ventilation.²⁷ Acute respiratory distress syndrome (ARDS) is a rare complication of TLS. Chest X-rays show diffuse, bilateral, pulmonary infiltrates. This complication can be managed using renal replacement therapy and intubation and ventilation. High levels of positive end-expiratory pressures and FIO2 may be required.^15,28

Ultimately, the management of TLS requires an integrated multidisciplinary team consisting of intensivists, nephrologists, and haemato-oncologists. The combination of skill sets allows for the appropriate management of TLS patients who often display multi-organ failure during their admission.

Prognosis and outcomes

Prognosis and outcomes vary greatly. A retrospective study looking at ICU admissions (for any cause) in 190 patients with newly diagnosed lymphoma found that around 80% of individuals were discharged from ICU, with a hospital mortality rate of 37%. Factors associated with increased mortality included age >50 years and a greater number of organ failures at time of ICU admission.²³

Another study found the in-hospital mortality from TLS to be 21%. Common complications included acute renal failure requiring dialysis, sepsis and respiratory failure.⁷ Acute renal failure at ICU admission in patients with TLS is associated with higher hospital mortality and 6-months mortality.²⁹ Furthermore, roughly 1 in 4 individuals with TLS develop an arrhythmia; most commonly atrial fibrillation followed by ventricular tachycardia. Those that developed arrhythmias were more likely to have electrolyte and fluid disturbances, and the presence of an arrythmia significantly increased the in-hospital mortality rate.³⁰ The presence of a solid tumour has also been associated with increased mortality and acute renal failure compared to other haematological cancers. It is postulated that this increased mortality is due to the fact that solid tumours may carry a higher tumour burden.^7,31

Earlier admission to ICU has been shown to reduce the need for mechanical ventilation and vasopressor support in patients with TLS secondary to AML. Earlier admission has also been associated with shorter ICU duration and increased survival.³² It has been suggested that in patients with a high risk of developing TLS, the possibility of starting chemotherapy in the ICU setting should be considered to enable close monitoring of electrolytes and fluid balance.

FICM syllabus

1.4: Triages and priorities patients appropriately, including timely admission to ICU

2.8: Integrates clinical findings with laboratory investigations to form a differential diagnosis

3.1: Manages the care of the critically ill patient with specific acute medical conditions

4.7: Initiates, manages, and weans patients from renal replacement therapy

4.8: Recognises and manages electrolyte, glucose, and acid-base disturbances

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Robert Chapman

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