Eosinophilia and Kidney Disease: More than Just an Incidental Finding?

Abstract

Peripheral blood eosinophilia (PBE), defined as 500 eosinophils or above per microliter (µL) blood, is a condition that is not uncommon but often neglected in the management of patients with chronic kidney disease (CKD), acute kidney injury (AKI), or patients on renal replacement therapy (RRT). The nature of PBE in the context of kidney diseases is predominantly secondary or reactive and has to be distinguished from primary eosinophilic disorders. Nonetheless, the finding of persistent PBE can be a useful clue for the differential diagnosis of underdiagnosed entities and overlapping syndromes, such as eosinophilic granulomatosis with polyangiitis (EGPA), IgG4-related disease (IgG4-RD), acute interstitial nephritis (AIN), or the hypereosinophilic syndrome (HES). For patients on RRT, PBE may be an indicator for bio-incompatibility of the dialysis material, acute allograft rejection, or Strongyloides hyperinfection. In a subset of patients with EGPA, eosinophils might even be the driving force in disease pathogenesis. This improved understanding is already being used to facilitate novel therapeutic options. Mepolizumab has been licensed for the management of EGPA and is applied with the aim to abrogate the underlying immunologic process by blocking interleukin-5. The current article provides an overview of different renal pathologies that are associated with PBE. Further scientific effort is required to understand the exact role and function of eosinophils in these disorders which may pave the way to improved interdisciplinary management of such patients.

Keywords: AKI; CKD; EGPA; IgG4-related disease; autoimmune disease; eosinophilia; interstitial nephritis; kidney disease; vasculitis.

Figure 1

Proposed overview and classification of eosinophilic disorders. Certain specific syndromes (grey boxes) in which the role of eosinophils in the disease mechanism are unclear should be differentiated from ‘real’ HES, according to the International Cooperative Working Group on Eosinophil Disorders (ICOG-EO) proposal (diseases in black letters are explicitly declared as such [2]). Different diseases leading to increased eosinophilic counts are sub-divided into hematologic, allergic, and infectious disorders, while idiopathic hypereosinophilic syndrome is separated from primary and secondary forms. IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; HE(S)_M, myeloid HE(S); HE(S)_L, lymphocyte-variant HE(S); CEL, chronic eosinophilic leukemia; NOS, not otherwise specified; CML, chronic myeloid leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; ALPS, autoimmune-lymphoproliferative syndrome; CTCL, cutaneous T-cell lymphoma; ALL, acute lymphocytic leukemia; LCH, Langerhans cell histiocytosis; NSAID, nonsteroidal anti-inflammatory drugs; PPI, proton-pump inhibitor; HIV, human immunodeficiency virus; HTLV, human T-lymphotropic virus; IgE, immunoglobulin E; CARD9, caspase recruitment domain-containing protein 9; SCID, severe combined immunodeficiency; EGPA, eosinophilic granulomatosis with polyangiitis; SLE, systemic lupus erythematosus; PAN, panarteritis nodosa; RA, rheumatoid arthritis; IgG4-RD, IgG4-related disease; EMS, eosinophilia myalgia syndrome.

Figure 2

Eosinophil granulomatosis with polyangiitis (EPGA) and overlapping syndromes. The clinical profile of EGPA has distinct but also overlapping symptoms. In the clinical assessment, specific investigations are often needed, since ANCA is negative in most patients. There is a clear overlap between EGPA with a predominant heart involvement and idiopathic hypereosinophilic syndrome (HES_I). On the other hand, polyangiitis overlap syndrome (POS) has been described for cases that fulfill diagnostic criteria for granulomatosis with polyangiitis (GPA) and EGPA and there is a particular overlap between microscopic polyangiitis (MPA) and EGPA in those with a positive ANCA test presenting with peripheral neuropathy and in some cases kidney and pulmonary disease. A clear distinction is not always possible but should be the aim of the initial investigation. Treatment approaches overlap in some situations. ANCA, anti-neutrophil cytoplasmic antibody; AAV, ANCA-associated vasculitis; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; POS, polyangiitis overlap syndrome; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose, and throat; HES, hypereosinophilic syndrome (I = idiopathic, R = reactive, N = neoplastic); PR3, proteinase 3; MPO, myeloperoxidase; IL-5, interleukin-5; FIP1L1-PDGFRA/B, gene fusion of fibroblast growth factor receptor 1 and platelet-derived growth factor receptor α/β; HLA, human leukocyte antigen; IVIG, intravenous immunoglobulins. According to the EGPA Consensus Task Force, glucocorticoids are the principal therapy to achieve EGPA remission, defined as absence of a clinical systemic manifestation (excluding asthma and/or ear, nose and throat manifestation). In life- and/or organ-threatening disease, remission-induction should include additional immunosuppression (e.g., cyclophosphamide). These patients usually need a maintenance therapy with azathioprine or methotrexate [26]. ANCA-positivity reflects activation of B-cells which could explain the good response seen in studies investigating the effect of RTX [73]. Given the retrospective analyses of RTX efficacy in EGPA, a lower grade of recommendation for the treatment has been issued compared to GPA/MPA according to the EULAR/ERA-EDTA recommendations [74,75,76]. In the largest trial of RTX in EGPA patients (41 cases) until now, Mohammad et al. showed good response rates after one year. Prednisolone could be reduced during follow-up. Interestingly, ANCA-positivity was found to be associated with a higher remission-rate at 12 months compared to ANCA-negative patients (80% vs. 36%) [77]. Other agents employed to reduce corticosteroid doses and maintain remission of EGPA include drugs targeting relevant pro-inflammatory components of the involved immune system. For example, omalizumab (anti-IgE antibody) and mepolizumab (anti-IL-5 antibody) are currently being investigated in several eosinophil disorders like asthma and HES [73]. One randomized controlled trial assigned patients either to mepolizumab or placebo and showed significant higher efficacy rates in the mepolizumab arm, which was achieved in approximately half of the mepolizumab-treated patients [78]—An observation that again adds fuel to the fire in the discussion about different disease phenotypes. Reslizumab and benralizumab are other antibodies targeting IL-5 and its receptor, being tested in phase II trials in patients with eosinophil-driven diseases, including EGPA (ClinicalTrials.gov identifier: NCT02947945; NCT03010436) [79]. In the so-far published clinical trials investigating anti-IL-5 targeted-therapy in EGPA patients, only one patient with glomerulonephritis was enrolled, partly because serum-creatinine elevations >2.5 mg/dL were excluded and renal involvement in EGPA is rare [78,80,81]. Therefore, no firm conclusions from the landmark trial on the effect of mepolizumab on renal impairment can be drawn. In general, renal involvement resembles similar histopathologic features as observed in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) with the absence of immune complexes (‘pauci-immune’) in most cases. A study investigating the efficacy of RTX in EGPA recruited patients with either >25% dysmorphic red cells, red cell casts, or biopsy-proven pauci-immune glomerulonephritis. Remission was defined as a composite of stabilization of renal function, absence of active urinary sediment and a significant reduction of the glucocorticoid exposure (<50% of the average dose received over three months before enrollment or <10 mg per day). Following treatment with RTX (375 mg/m²/week × 4) patients achieved renal remission which was prolonged during a follow-up period of 12 months [82]. Clinical trials particularly looking at renal disease in the context of EGPA are highly desirable, but recruitment of such patients remains difficult, partly because only one-quarter of EGPA patients present with renal involvement and most are not managed by nephrologists.

Figure 3

Proposed approach for the initial management of unexplained eosinophilia. When PBE is detected, a systematic management should include a basic assessment, an evaluation of urgency, and the screening for organ dysfunctions. EC, eosinophil count; HE, hypereosinophilia; HES, hypereosinophilic syndrome; RFT, renal function tests; LFT, liver function tests; FACS, fluorescence-activated cell scanning; ECG, electrocardiogram.

Figure 4

Proposed approach for the management of PBE and AKI. A three-step approach is suggested for the assessment and differential diagnosis. Drug-induced AIN (bold letters) is a comparably frequent finding and prompt identification of the culprit drug is decisive for prognosis. PBE, peripheral blood eosinophilia; AKI, acute kidney injury; HE, hypereosinophilia; EC, eosinophil count; eGFR, estimated glomerular filtration rate; PCR, protein-creatinine ratio; ACR albumin-creatinine ratio; ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; anti-PLA2R-AB, anti-phospholipase-A2-receptor antibody; IgG, immunoglobulin G; EGPA, eosinophilic granulomatosis with polyangiitis; IgG4-RD, IgG4-related disease; TINU, tubulointerstitial nephritis and uveitis; AIN, acute interstitial nephritis; CES, cholesterol embolization syndrome; TMA, thrombotic microangiopathy; HES, hypereosinophilic syndrome.