Differentiation Syndrome Presenting as Acute Kidney Injury in a Patient of Acute Promyelocytic Leukemia on All-trans Retinoic Acid and Arsenic Trioxide Regimen: A Case Report

Abstract

Introduction:

Acute promyelocytic leukemia (APL), classified as Subtype M3 of acute myeloid leukemia, is known for its relatively favorable prognosis, primarily due to the high effectiveness of all-trans retinoic acid (ATRA) in treating the maturation block. However, it is essential to be aware of potential complications such as ATRA syndrome, which can affect 5%–25% of patients and manifest with symptoms such as fever, interstitial pulmonary infiltration, pleural/pericardial effusion, and acute renal failure.

Methods:

We present the case of a 47-year-old female with a history of hypertension, who experienced rash, fever, and reduced urine output during the induction phase with ATRA. Her serum creatinine levels exhibited a rapid increase from 2.63 mg/dL on October 07, 2022, to 7 mg/dL on October 18, 2022, despite having normal-sized kidneys and normal corticomedullary differentiation. A renal biopsy conducted on October 20, 2022, revealed features consistent with active tubulointerstitial nephritis, with direct immunofluorescence showing no significant glomerular immune deposits. A total of 17 hemodialysis sessions were performed.

Results:

A subsequent bone marrow examination conducted on October 26, 2022, demonstrated a hypercellular aspirate with normal morphology. However, due to the persistence of renal failure, a repeat biopsy was performed, revealing severe acute tubular injury. Pulse steroids were initiated, and ATRA was discontinued, resulting in an improvement in renal function.

Conclusion:

This case highlights an instance of acute, early, and severe differentiation syndrome (DS) occurring after induction therapy in a patient with APL. The DS in this case was particularly severe, leading to renal failure necessitating hemodialysis. The prompt initiation of pulse steroids and discontinuation of ATRA proved to be effective in managing this complication. Clinicians should remain vigilant for DS and its potential complications, including acute kidney injury and acute tubulointerstitial nephritis, when treating patients with APL.

Introduction

Acute tubulointerstitial nephritis (ATIN) is a condition characterized by histologic findings of interstitial inflammatory cellular infiltrate, variable degrees of tubular injury, interstitial edema, and tubulitis.^[1] The clinical presentation of ATIN can range from hospital-acquired acute kidney injury (AKI) to a subacute decline in kidney function or solely abnormal urinary findings such as hematuria, pyuria, or proteinuria. Although the classical triad of ATIN (fever, rash, and eosinophilia) is rarely observed, drug-induced ATIN remains the most common underlying cause.

Differentiation syndrome (DS), formerly known as retinoic acid syndrome or all-trans retinoic acid (ATRA)/arsenic trioxide (ATO) syndrome, is a complication or side effect that occurs in patients with acute promyelocytic leukemia (APL), a rare subtype of acute myeloid leukemia (AML). APL represents a hematological emergency.^[2] DS manifests after induction therapy with differentiating agents, such as ATRA or ATO,^[3] and is characterized by symptoms including fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, chronic renal failure (CRF), and acute renal failure (ARF).^[4] The treatment for DS involves early intravenous administration of steroids to counteract the cytokine storm responsible for its development. This is a rare condition where early recognition and therapy are crucial for a favorable prognosis.^[5]

Case Report

A 47-year-old female patient, hypertensive, and newly detected diabetic was admitted with a short 7 days history of fever, reddish spots, and patches on both the lower limbs and decreased urine output of 2 days. She was recently diagnosed to be a case of APL by bone marrow aspiration (BMA) + biopsy and was started on Cap ATRA since September 12, 2022, and injection ATO September 15, 2022. There was no history of hemoptysis, joint pain, photosensitive pain abdomen, hematuria, orthpnoea, nor any suggestive history of pain abdomen, hematuria, orthopnoea, nor any suggestive history of recent infection. There was no other significant medical history. Family and socioeconomic history were noncontributory. There was no other drug history nor was she allergic to any known substance till date.

Physical examination of the patient was notable for presence of pallor, edema, diffuse darkening of skin, petechiae, and purpura in bilateral lower limb and inner thigh. Other findings on examination were, otherwise, unremarkable.

Laboratory values on admission were notable for a serum creatinine of 2.63 mg/dL, hemoglobin (Hb) = 5.5 g/dL, Total WBC count (TC) = 1000 cell/mm³, and platelet = 46,000 cell/mm³, and peripheral blood smear showed atypical mononuclear cells and uric acid = 10.1 mg/dL. Urine analysis showed plenty of red blood cells (RBCs) with nil proteinuria, while liver function test (LFT) and electrolytes were within normal ranges. These, lab values, in addition to patient volume status and vital signs were important in distinguishing prerenal causes from intrinsic renal causes. Renal ultrasonography (USG) showed a right kidney measuring 11 cm, left kidney 11.3 cm with normal echo, and corticomedullary differentiation.

Upon revisiting the patient’s medical records, she had a normal renal function before the disease, which rapidly increased to 7.37 mg/dL till October 18, 2022. Regular thrice-weekly hemodialysis was initiated on October 19, 2022. The patient underwent USG-guided renal biopsy on October 20, 2022.

The renal biopsy clinched the diagnosis for the patient on microscopy; the viable glomerular areas revealed nonproliferative morphology. 10% of sampled cortex shows interstitial fibrosis with tubular atrophy (IFTA); tubules show prominent cytoplasmic vacuolar change and severe acute injury. Scattered inspissated hyaline, granular, and many RBC casts were seen in tubular lumina.

Tissue for direct immunofluorescence of renal cortical area was negative. Concurrently, a repeat bone marrow examination was done on October 26, 2022, for response assessment of primary malignancy which was suggestive of hypercellular aspirate, trilineage hematopoiesis with normal morphology.

Results

The patient underwent a total of 17 hemodialysis sessions over the course of 1½ months. Despite the removal of probable causes of AKI, renal failure persisted. As a result, a repeat renal biopsy was performed, which indicated severe acute tubular injury with nonproliferative morphology in the sampled cortex.

In response to these findings, pulse steroids were administered, and the use of ATRA was discontinued. Following this intervention, the patient’s renal function gradually improved, with serum creatinine levels decreasing to 1.9 mg/dL.

The patient is currently in a clinically stable condition and no longer requires dialysis. In addition, a repeat analysis for the presence of promyelocytic leukaemia/retinoic acid receptor alpha (PML-RARα) was negative, and a repeat BMA showed normal results.

Discussion

APL represents a unique and relatively rare variant of AML, constituting approximately 5%–10% of all newly diagnosed AML cases. APL is often associated with coagulation disorders. The aggressive treatment of APL, primarily with potent drugs such as ATRA and ATO, has significantly improved disease prognosis and outcomes.

However, the management of APL can be complicated by the development of DS, a potentially life-threatening complication that typically occurs after treatment with ATRA and/or ATO. DS manifests with symptoms such as fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, and/or ARF, primarily due to capillary leakage and CRF. Patients with blood malignancies are often at risk of AKI in the context of sepsis, nephrotic syndrome, and hypovolemia.

Studies, such as that by Kamio et al.,^[6] have reported that the incidence of AKI during induction therapy with ATRA and/or ATO in newly diagnosed APL is approximately 40%. Furthermore, a research by Chamoun et al.^[7] identified advanced age, elevated serum creatinine levels, low Hb counts, and hypoalbuminemia as significant predictors of poor prognosis and early mortality in patients with APL undergoing ATRA and ATO therapy.

Conclusion

Our case study underscores the importance of early recognition and management of DS, which represents a complex and unpredictable complication of APL treatment with ATRA and ATO. It typically emerges within days to weeks during induction therapy, although it is extremely rare during maintenance therapy, underscoring the need for vigilance during this specific treatment phase. The absence of specific laboratory tests or clinical examinations for DS diagnosis highlights the importance of recognizing clinical symptoms promptly. Effective management hinges on timely intervention, including ventilation support, steroid administration, and, in severe cases, temporary discontinuation of ATRA or ATO therapy until clinical recovery. Early recognition of DS symptoms is paramount in reducing morbidity and mortality risks, emphasizing the importance of patient and family education. A multidisciplinary approach, involving hematologists, intensivists, and critical care teams, is essential for optimal care, fostering collaboration, and communication among specialists. These comprehensive considerations provide a foundation for addressing the challenges and strategies associated with DS in APL treatment with ATRA/ATO.

In conclusion, the key to reducing morbidity and mortality associated with DS lies in the early recognition of its symptoms and the prompt institution of appropriate supportive measures and steroid therapy.