Hemophagocytic syndromes (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), represent an immune dysfunction characterized by an exaggerated and pathological inflammatory response, resulting in hypercytokinemia and potential multiorgan failure. This condition can lead to significant damage in target organs, with acute kidney injury (AKI) being particularly noteworthy as a strong predictor of poor prognosis. Morbidity in HLH patients, reaching up to 50%, underscores the severity of the disease (1–4). Given its rapid progression and high mortality rates (5, 6), early diagnosis and intervention are pivotal for improving patient outcomes.

Recognizing the critical role of renal involvement, especially AKI, it becomes imperative to comprehend the clinical presentation, diagnosis, and treatment of HLH. Identifying high-risk factors for AKI in HLH patients and promptly admitting them to intensive care units for intervention are essential components of patient care. Unfortunately, the early recognition of AKI in HLH patients is presently underestimated, with limited reported studies. A comprehensive understanding of the incidence, clinical features, and prognosis of AKI in HLH patients is still lacking. Addressing these gaps in knowledge is crucial for enhancing the overall management and prognosis of patients with HLH.

In summary, this article provides an overview of the clinical manifestations, underlying causes, biomarkers, immunopathogenesis, and management strategies for patients presenting with hemophagocytic syndrome complicated by acute kidney injury (AKI), intended to assist clinicians in their understanding and management of this condition.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and inadequately diagnosed disease with an unknown true prevalence due to the non-specific nature of its clinical presentation. Consequently, the epidemiology of HLH-associated acute kidney injury (HLH-AKI) remains poorly characterized.

First documented by Scott and Robb-Smith in 1939, HLH is a syndrome characterized by fever, hepatosplenomegaly, peripheral hypoplasia, and macrophage proliferation in the bone marrow and other hematopoietic organs (7). The initial familial case was reported by Farquhar in 1952 (8), and infection-associated HLH was recognized as a distinct clinical and pathologic feature in 1979 (9). The term “Hemophagocytic lymphohistiocytosis” was officially adopted by the International Histiocyte Association in 1991 (10).

The clinical presentation of HLH is heterogeneous, constituting a group of diseases marked by prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia. It is characterized by histiocyte proliferation and increased hemophagocytosis. The HLH-2004 criteria (11) remain internationally recognized for diagnosis ( Table 1 ) but are more tailored to pediatric cases and have limitations when applied to adults. The 2023 HiHASC guidelines (12) propose rapid identification markers, such as fever, decreased blood counts, and elevated ferritin levels; ferritin thresholds are not the same in adults and children. The guidelines recommend that the quick screen should be available within 6 h–12 h. Confirmation of HLH diagnosis and investigation into potential triggers or underlying causes should be completed within the subsequent 24 h–48 h. Among the scoring systems utilized to assess HLH probability in patients, the H-score is presently deemed most suitable for adults (13). It incorporates three clinical variables (underlying immunosuppression, fever, organomegaly), five routine blood tests (ferritin, triglycerides, aspartate aminotransferase, fibrinogen, and cytopenias), and one histopathologic factor (tissue phagocytosis), resulting in a total score of 337 points. The probability of diagnosing HLH exceeds 99% for scores exceeding 250, with a cutoff value of 169. With ongoing improvements in clinical diagnosis leading to increased case identification, secondary HLH is more frequently diagnosed. It often occurs in conjunction with various underlying disease states, particularly in patients with malignant tumors, severe infections, and various critical illnesses causing organ dysfunction, including renal impairment. HLH secondary to rheumatic diseases, is designated as macrophage activation syndrome (MAS). MAS, a subtype of HLH, represents a severe complication of rheumatic diseases, arising from the dysregulated activation and proliferation of T lymphocytes and macrophages. MAS, particularly with heightened phagocytic activity, presents a grave and potentially lethal condition. Rheumatic disorders implicated in MAS encompass systemic juvenile idiopathic arthritis (SJIA), systemic lupus erythematosus (SLE), Kawasaki disease (KD), and dermatomyositis, each characterized by clinical features indicative of HLH. Secondary HLH manifests through diverse etiologies, as outlined in Table 2 , detailing the underlying diseases contributing to HLH development (14).

However, discerning patients with hemophagocytic lymphohistiocytosis (HLH) from those experiencing severe sepsis presents a formidable clinical challenge. While experienced hematologists typically conduct early screening for suspected HLH cases, routine assessments for the majority of critically ill patients with similar clinical presentations rarely include specialized tests such as sCD25 and NK cell activity. This limited utilization of advanced diagnostic tools may result in the oversight or delayed diagnosis of HLH in a subset of patients, contributing to the rapid progression of the syndrome and elevated rates of morbidity and mortality. Incorporating these specialized tests into routine evaluations for critically ill patients with risk factors could enhance diagnostic accuracy, facilitating more timely interventions and potentially improving outcomes in cases of HLH.

Secondary HLH, particularly when induced by infection, closely aligns with the definition of sepsis, manifesting as organ dysfunction triggered by a cytokine storm. Due to their overlapping features, approximately one-fifth of septic patients may exhibit characteristics resembling HLH (15). In cases of septic shock, misdiagnosis with HLH is not uncommon (16) and the diagnosis of HLH is not sufficient for patients admitted to the ICU (17). Routine diagnostic evaluations of patients with systemic inflammatory syndromes at the Mayo Clinic have revealed that the prevalence of HLH in sepsis patients can be as high as 1 in 2000 (18). Notably, the phenomenon of tissue phagocytosis lacks sensitivity and specificity, making it challenging to differentiate between secondary HLH and sepsis. Phagocytosis is also observed in a subset of sepsis cases, complicating the distinction between phagocytosis directly induced by sepsis versus that triggered by sepsis-associated secondary HLH (17, 19, 20). In a multinational study involving 362 patients with systemic juvenile idiopathic arthritis (JIA) complicated by macrophage activation syndrome (MAS), phagocytosis was identified in only 60.7% of patients upon bone marrow examination (21). This underscores the complexity of the relationship between infection and HLH. The intricate relationship between HLH and sepsis is compounded by HLH’s inherent immune dysregulation. Moreover, chemotherapy and immunosuppressive treatments exacerbate mucosal damage, intensify immune dysfunction, and induce cytopenias, rendering patients more vulnerable to secondary infections. A study noted that 56% of HLH patients exhibited concurrent infections, with 67% succumbing directly to infectious complications (22).

HLH can be further complicated by infections during treatment due to immunosuppression. Additionally, infections can give rise to reactive hemophagocytic syndrome (RHS) (23), which may contribute to multiple-organ dysfunction syndrome (MODS). Both HLH and RHS may occur simultaneously, potentially triggered by the same cytokines. However, there is currently insufficient evidence to support a direct causal relationship between the two.

Regrettably, there is no specific diagnostic test for HLH and diagnosis continues to rely on clinical presentation. Efforts to enhance diagnostic precision in critically ill patients, particularly those with overlapping symptoms of HLH and sepsis, remain a critical area for future research.

Therefore, we propose several features that may distinguish HLH from sepsis:

These proposed features aim to facilitate the differentiation between HLH and sepsis, providing clinicians with valuable clinical indicators to enhance diagnostic accuracy, especially in critically ill patients.

The etiology of HLH-AKI, characterized by acute kidney injury complicated by phagocytic syndrome, can be broadly categorized into direct injury by inflammatory mediators, hemodynamic instability, tumor-associated renal injury, and the application of nephrotoxic drugs. It is challenging to pinpoint the specific cause of AKI, as it may involve multiple factors simultaneously.

Familial cases of HLH reported in the literature highlight activated macrophage infiltration as a direct consequence of specific renal parenchymal involvement (33). These cases confirm that HLH induces direct inflammatory damage to the kidneys. Patients in these familial cases responded well to high-dose intravenous glucocorticoids and continuous blood purification, showing a reversible transition from renal injury.

Secondary HLH, frequently triggered by infectious diseases, constitutes 44.5% of the etiology (34), with viruses, particularly herpesviruses like EBV and CMV, being predominant pathogens. Severe infectious cases can precipitate septic shock, resulting in renal hypoperfusion. Concurrently, the amplified cascade of inflammatory responses, triggered by severe infections, prompts the release of diverse inflammatory factors directly affecting the kidneys. This cascade leads to renal dysfunction, suggesting that the primary cause of acute kidney injury (AKI) is attributable to both renal hypoperfusion and the direct impact of inflammatory mediators on kidney function. Aulagnon et al. reported that hypoperfusion was the second-highest contributor to AKI etiology in 95 cases of secondary HLH, with most patients experiencing renal dysfunction at KDIGO stages 2 or 3 (31).

In patients with hematologic malignancies, AKI accounts for 35% of the etiology (34), primarily associated with B-cell lymphoma. Tumor-induced monoclonal gammopathy, renal injury due to malignant cell infiltration, and paraneoplastic tumors are potential AKI causes (35). Prerenal and acute tubular necrosis are common, often stemming from the direct effects of tumors, tumor complications, and chemotherapy.

Examination-related drugs, antitumor drugs, and anti-infective drugs used in diagnosis and treatment are frequently nephrotoxic, contributing to AKI in HLH patients. Previous exposure to nephrotoxic drugs has been reported in 72.3% of AKI patients (2), involving agents such as contrast agents, vancomycin, aminoglycosides, and nonsteroidal anti-inflammatory drugs, as well as methotrexate, siderophores, cyclophosphamide, and oxaliplatin. Recommended therapy for HLH include chemotherapy such as etoposide, which is cleared by the kidney.

Primary HLH predominantly affects children, and immune dysfunction is typically irreversible. The primary cause is often autosomal recessive, resulting from defects in the release of cytoplasmic granules containing enzymes like perforin and granzyme B by cytotoxic T cells and NK cells. HLH leads to compromised cytotoxic T-cell and natural killer (NK) cell functionality. Pathogenic mutations in four genes (PRF1, UNC13D, STX11, and STXBP2) are identified (36–39), all impacting the perforin pathway crucial for lymphocyte cytotoxicity. These enzymes are crucial for cytotoxic activity, and their deficiency leads to uncontrolled proliferation of lymphocytes and macrophages. The subsequent phagocytosis is amplified by the excessive production of pro-inflammatory cytokines ( Figures 1 , 2 ).

Secondary HLH, more prevalent in adults, is triggered by infections, malignancies, and autoinflammatory/immune disorders. Infections are the most common cause, with the initial response coming from activation of antigen-presenting cells (APC), initiating a TH-1 response that induces cytotoxic T cells and NK cells to proliferate. Reversible dysfunction of NK or CD8+ T cells characterizes immune dysfunction. The release of interferon (IFN) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by cytotoxic T cells leads to sustained expansion and activation of cytotoxic CD8+ T cells and macrophages, histiocyte proliferation, and infiltration into organs, including the kidneys. Renal infiltration of activated cytotoxic T cells and macrophages is recognized as a potential mechanism of AKI (40). Inflammatory factors such as TNF, IL-1, and IL-6 contribute to a cytokine storm, resulting in tissue damage, severe systemic inflammatory response syndrome (SIRS), and multiorgan failure (41) ( Figure 3 ).

Both primary and secondary HLH involve an overactivation of the immune response, causing a cytokine storm that can lead to multiple-organ insufficiencies, including renal complications. Hallmarks of HLH include bone marrow infiltration and the presence of non-malignant macrophages in organs. Non-malignant macrophages, associated with phagocytic activity, can affect various kidney structures. In HLH-AKI, tubular involvement is prevalent (31), often manifesting as acute tubular necrosis, with an incidence of up to 62%. The majority of AKI cases progress to KDIGO 2 or KDIGO 3. Histopathological alterations reveal acute tubular necrosis accompanied by interstitial inflammation, observed in 45% of HLH patients (1). Tubulointerstitial damage may arise from hemodynamic shifts and coagulation disorders during the acute phase of severe sepsis. While glomerular involvement is infrequent, it can lead to collapsed glomerulopathy, focal segmental glomerulosclerosis, microscopic lesions, and thrombotic microangiopathy (3, 42–44). A direct deleterious effect of pro-inflammatory cytokines on the kidney is evident. Observations suggest that the direct toxic impact of pro-inflammatory cytokines (IL-6 and TNF-α) on renal tubular cells may be a mechanism in the development of AKI in HLH (1). Glomerular hemophagocytic macrophages may locally release nephrotoxic cytokines (45), inducing dysfunction in the local glomerular capillary wall and resulting in protein leakage, leading to proteinuria and renal dysfunction. Infiltration of the renal parenchyma by activated macrophages can contribute to reversible AKI (33).

Given the substantial morbidity and mortality associated with HLH-AKI and its non-specific clinical presentation, clinicians face a significant challenge in timely diagnosis and treatment. To enhance early identification of this patient group and improve clinical outcomes, various biomarkers have been reported. However, these biomarkers are often case-specific, lacking a standardized marker for accurate identification. Based on recent reports, we summarize the current understanding of these biomarkers as follows ( Table 4 ).

No singular biomarker effectively distinguishes between HLH and sepsis; however, some studies explore combined biomarkers providing insights into the differential diagnosis. A distinctive cytokine profile characterized by markedly elevated levels of IFN-γ and IL-10, coupled with moderately elevated IL-6 levels, exhibits high diagnostic accuracy for HLH (48). This cytokine pattern aids in distinguishing HLH from infection. Additionally, the cytokine profile consisting of IL-18, IL-1β, and IFN-γ demonstrates good sensitivity and specificity in identifying severe infections (84).

In conclusion, whereas various biomarkers show promise in aiding HLH diagnosis, the lack of a standardized marker necessitates ongoing research and validation through large-scale prospective studies.

Despite the similarities between HLH and sepsis, including multiorgan dysfunction and similar clinical features, their treatment approaches differ significantly. HLH treatment focuses on repetitive chemotherapy to eliminate immune activation stimuli and suppress hypercytokinemia, patients with rapid clinical deterioration are the target population for HLH chemotherapy, and potential triggers need to be identified and treated in patients whose clinical status is stable, whereas sepsis treatment primarily relies on anti-infective therapy and intensive symptomatic care ( Table 5 , Figure 4 ).

Timely diagnosis plays a pivotal role in the identification and management of patients with hemophagocytic lymphohistiocytosis (HLH), facilitating the reversal of renal impairment and creating a therapeutic window for HLH intervention. Collaborative efforts involving hematologists, intensivists, and nephrologists are essential for a comprehensive understanding of HLH pathogenesis, early identification of critically ill patients, prompt initiation of immunomodulatory therapy, and the optimization of organ supportive care. These measures hold the potential to enhance the prognosis and increase the complete remission rate among patients with HLH. Future research endeavors should focus on further unraveling the complexities of HLH and refining multidisciplinary approaches for improved patient outcomes.

MZ: Writing – original draft, Conceptualization. YG: Writing – original draft, Visualization. JL: Writing – review & editing, Supervision. YQ: Writing – review & editing, Validation. SZ: Writing – review & editing, Validation, Supervision. MD: Writing – review & editing.