Introduction

Idiopathic hypereosinophilic syndrome (HES) is characterized by an absolute eosinophil count greater than 1500 cells/mm3 observed at least twice with a minimum interval of 4 weeks, multiorgan involvement, and presence of tissue damage without an identifiable underlying cause [1]. Renal involvement in HES varies from 7% to 36%; however, kidney injury mediated by thrombotic microangiopathy (TMA) is rare [2]. To the best of our knowledge, only two cases of idiopathic HES [3] and one case of myeloproliferative-variant HES [4] have been reported. None of the reported cases achieved normal kidney function after treatment. The pathophysiology of renal impairment in HES can be explained by two mechanisms: (1) an ischemic kidney injury secondary to cardiac mural thrombus mediated by eosinophilic cytotoxicity to the heart (endocardium and myocardium) and (2) direct eosinophilic cytotoxic effect to the kidney [2,3,4,5]. We present a rare case of idiopathic HES with multiorgan failure and renal biopsy-proven TMA in which complete remission was achieved after 8 weeks of steroid therapy.

Case presentation

A 63-year-old Caucasian man presented to our hospital with 2 weeks of progressive generalized weakness, vague abdominal discomfort, and dyspnea on exertion requiring more frequent use of his inhaler. He did not report similar symptoms in the past, and he denied any associated chest pain, cough, changes in bowel habits, fevers, chills, weight loss, recent travel, tick bites, or sick contacts. His past medical history was relevant for chronic bronchitis diagnosed 10 years ago. He was a former one-pack-per-day smoker for 20 years. His family history was noncontributory.

Clinical findings

The patient’s vital signs at presentation showed a blood pressure of 128/84 mmHg, heart rate of 75 beats/minute, respiratory rate of 18 breaths/minute, oxygen saturation of 99% on room air, and body temperature of 97.7 °F. On physical examination, the patient was in no apparent distress and was awake, alert, and oriented to person, place, and time. His heart and lung examination revealed sinus tachycardia and diffuse expiratory wheezes throughout the lung fields. The patient’s abdominal examination was pertinent for a nonperitonitic tenderness to palpation in the left upper quadrant. His neurological examination was remarkable for weakness in the right upper extremity. His laboratory data are summarized in Table 1.

Table 1 Laboratory data during hospitalization
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Timeline

See Fig. 1 for the timeline of the patient’s kidney function and absolute eosinophil count while receiving steroid treatment.

Fig. 1
figure 1

Kidney function and absolute eosinophil count evolution on steroid treatment. GFR Glomerular Filtration Rate

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Diagnostic assessment

Findings of computed tomography (CT) of the patient’s brain were unremarkable. Magnetic resonance imaging (MRI) of his brain revealed subacute infarcts involving the left frontal white matter and left cerebellum; in addition, an evolving subacute infarct was seen in the left corona radiata. CT of the chest demonstrated diffuse ground-glass opacity, and CT of the abdomen was remarkable for a wedge-shaped area of low attenuation in the spleen consistent with splenic infarct. His transthoracic echocardiogram revealed a mural apical thrombus in the left ventricular (LV) apex with reduced ejection fraction (31–35%). Cardiac MRI performed 7 days after anticoagulation therapy was initiated showed a diffuse subendocardial scarring of the middle to apical LV segments and the right ventricular side of the septum. It also revealed evidence of edema of the middle anteroseptum and apical septum, consistent with endomyocardial fibrosis. However, no mural thrombus was visualized.

A presumptive diagnosis of HES was made on the basis of presenting symptoms, laboratory data, and imaging studies. Investigation for secondary causes, including immunological testing (Table 2), blood and urine cultures, ova and parasites, and infectious serology (Table 3), were unrevealing, and results of urine drug screening were negative. Bone marrow biopsy demonstrated a normocellular bone marrow population with eosinophilia comprising 60–70%, without evidence of lymphoproliferative disorder or metastatic neoplasm. Cytogenetic analysis was unrevealing: negative for breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) fusion, eosinophilia-associated platelet-derived growth factor receptor alpha (PDGFRA), platelet-derived growth factor receptor beta (PDGFRB), fibroblast growth factor receptor 1 (FGFR1), Janus kinase 2 (JAK2) mutation, and JAK2 pericentriolar material 1 (PCM1) fusion.

Table 2 Immunological test results
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Table 3 Infectious disease test results
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Due to the stigma of hemolysis (normocytic acute anemia, elevated lactate dehydrogenase and bilirubin, positive schistocytes with relative thrombocytopenia), further investigation was pursued. The result of the Coombs test (direct and indirect) was negative. A disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) activity level was greater than 50%, and the expression of complement regulatory proteins CD59 and CD55 on erythrocytes was within normal limits as determined by flow cytometry.

Due to a further decline in the estimated glomerular filtration rate (GFR) early in the patient’s hospital course, a kidney biopsy was pursued. Renal biopsy revealed a glomerular and vascular TMA, interstitial fibrosis, and inflammation with focal eosinophils (Fig. 1). IHC staining for eosinophil granule major basic protein 1 (MBP1) was not performed.

Therapeutic intervention

Our patient was started on prednisone 1 mg/kg daily and a heparin protocol at 18 U/kg/hour with an activated partial thromboplastin time goal of 60–100 seconds. Simultaneously, warfarin was initiated. Once the patient’s international normalized ratio was within therapeutic range (2.0–3.0), he was anticoagulated with heparin and warfarin for an additional 48 hours. His eosinophil count and estimated GFR were monitored on an outpatient basis, and his prednisone dose was gradually tapered. After the eighth week, the patient was maintained on 5 mg of prednisone daily.

Follow-up and outcomes

By the time the renal biopsy report was available, the patient’s kidney function had started to recover; hence, no further intervention was required. After initiation of treatment with steroids, the patient achieved resolution of pulmonary, cardiac, neurologic, and abdominal symptoms. Repeat echocardiography after 5 weeks showed improvement of LV ejection fraction to 50–55%. Complete normalization of eosinophil count and renal function was observed after 4 and 8 weeks of therapy, respectively (Fig. 1). At his 10-week follow-up, the patient continued to do well under close surveillance for renal and cardiac complications. At 12-month follow-up, he continued to have a normal eosinophil count and renal function. However, cardiac MRI showed persistent endocardial fibrosis.

Discussion

HES is an uncommon disorder, marked by overproduction of eosinophils, eosinophilia greater than 1500/mm3, tissue infiltration, and organ damage. Idiopathic HES requires exclusion of primary and secondary causes of hypereosinophilia as well as lymphocyte-variant hypereosinophilia [1]. For the period from 2001 to 2005, the National Cancer Institute Surveillance, Epidemiology, and End Results Program reported an age-adjusted incidence of 0.036 per 100,000 person-years for myeloproliferative HES. The incidence of idiopathic HES remains obscure [6]. The most common presenting symptoms are weakness, fatigue, cough, and dyspnea, followed by fever, rash, rhinitis, and in rare cases angioedema [7]. The mortality of HES is close to 10%, with the leading cause of death attributed to cardiac events followed by thromboembolic phenomena [8].

The pathogenesis of HES is mediated by “piecemeal degranulation” or eosinophil activation and secretion of the granule cationic proteins (such as eosinophil peroxidase, eosinophil cationic protein, eosinophil-derived neurotoxin, and MBP1) and eosinophil-expressed cytokines (such as RANTES [regulated on activation, normal T expressed and secreted] and interleukin [4, 9]). Eosinophil granule cationic proteins have the capability to activate inflammatory cells such as mast cells to induce inflammatory mediators and direct tissue-damaging cytotoxicity. These multiple proinflammatory activities lead to endothelial damage, thrombosis by activation of complement and coagulation cascade, and direct platelet stimulation and downregulation of thrombomodulin by MBP1 [5, 9].

Renal involvement in idiopathic HES is a rare entity, with only a handful of cases reported in the medical literature (Table 4) [10,11,12,13,14,15,16,17,18,19,20,21]. TMA is a life-threatening syndrome of systemic microvascular occlusions and is characterized by sudden or gradual onset of thrombocytopenia, microangiopathic hemolytic anemia, and renal or other end-organ damage [22]. It has been associated with diverse diseases and syndromes, such as systemic infections, cancer, pregnancy complications (for example, preeclampsia, eclampsia, HELLP [hemolysis, elevated liver enzymes, low platelet count] syndrome), autoimmune disorders (for example, systemic lupus erythematosus, systemic sclerosis, antiphospholipid syndrome), hematopoietic stem cell or organ transplant, severe hypertension, and cocaine-induced [22, 23]. Liapis et al. first reported two cases of TMA associated with idiopathic HES, along with a third case of myeloproliferative variant of HES in association with TMA [3] (Table 5). Of the cases described by Liapis et al., none had full renal recovery. In contrast, our patient did remarkably well with steroid and anticoagulation therapy. After discharge, his eosinophil count remained stable with resolution of renal injury with prednisone.

Table 4 Renal pathology in hypereosinophilia
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Table 5 Reported thrombotic microangiopathy cases: comparative table
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The mechanism of kidney damage in TMA with HES can occur via two different pathways: (1) direct eosinophilic cytotoxic effects to the renal vasculature and (2) ischemia secondary to thromboembolic events due to endocardial disruption. Subsequently, endothelial damage and complement cascade activation will result in TMA [1, 2, 5]. Similarly to our patient’s case and cases reported previously, Spry [10] reported that one of every five patients with HES developed hypertension and some degree of proteinuria. However, the described patients presented late in the course of HES and most likely had ischemic changes to the kidney secondary to cardioembolism rather than intrinsic eosinophilic cytotoxicity [2].

A multicenter analysis demonstrated that steroids alone induced partial or complete response at 4 weeks of treatment in 85% of the patients [24]. It was also observed that patients with positive factor interacting with PAPOLA [poly(A) polymerase alpha] and CPSF1 (cleavage and polyadenylation specificity factor) (FIP1L1)–PDGFRA gene fusion had a higher response to imatinib than those without [24]. It has been hypothesized that the deletion of genetic material as occurs in HES may result in gain of fusion proteins [25].

We report the only patient treated solely with a steroid, and a complete resolution of acute kidney injury was achieved, in contrast to previously reported cases. We hypothesize that factors such as the patient’s age group, proteinuria, and relative thrombocytopenia might be important to consider as prognostic factors.

Conclusion

TMA of the kidney in association with idiopathic HES is rare. To the best of our knowledge, this is the first case report of HES with multiorgan involvement that was successfully treated with a corticosteroid alone. Further studies are needed to investigate if age, absence of frank thrombocytopenia, and proteinuria can serve as prognostic features, as seen in our patient’s case.