Atheroembolic Kidney Disease and Atypical Hemolytic Uremic Syndrome: Two Sides of the Same Coin?

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by the hyperactivation of the alternative complement pathway, leading to a prothrombotic and proinflammatory state on the endothelial surface. It results in the formation of fibrin deposits and microthrombi in arterioles and capillaries. Generally, the onset is acute and characterized by the classic triad of thrombotic microangiopathy: non-autoimmune microangiopathic hemolytic anemia, thrombocytopenia with normal coagulation profile, and acute renal failure [1].

Atheroembolic kidney disease (AEKD) is known as the “silent killer” just because it is an under-recognized cause of kidney failure, secondary to the obstruction of the renal artery and/or its branches due to the rupture of an unstable (or damaged) atherosclerotic plaque, typically located in descending thoracic or abdominal aorta. When patients affected by systemic atherosclerosis are treated with surgical and invasive cardiovascular procedures [2], or hemodynamic stress induced by anticoagulant or fibrinolytic therapy, preexisting plaques are exposed to mechanical stress which break down the fibrous cap and leave the cholesterol-rich lipid core exposed. The consequent embolization of cholesterol crystals in the renal artery is followed by their deposition on the endothelium of the downstream vasculature, which activates the complement and triggers an inflammatory reaction. These events lead to macrophage and giant cell infiltration, intimal proliferation, intravascular fibrosis, and subsequent blood flow reduction with tissue necrosis. To our knowledge, this is the first case of aHUS secondary to a subacute AEKD. Further studies are necessary to fill the gap in the knowledge of the precise mechanism and to confirm that they are two sides of the same coin.

On February 2024, a 72-year-old man was referred to our clinic because of a rapid worsening of renal function. He has already suffered from stage 3b chronic kidney disease (CKD) (serum creatinine 1.8 mg/dL, eGFR CKD-EPI 35 mL/min/1.73 m²) with unknown etiology for many years; he denied a previous episode of HUS; he was affected by arterial hypertension for at least 5 years, diabetes mellitus type 2 for 2 years, treated with linagliptin, dyslipidemia treated with ezetimibe/simvastatin, and he was a heavy smoker till some years before. His clinical condition was stable till April 2023 when he was accidently diagnosed with an aneurysm of the subrenal abdominal aorta, extended to the iliac bifurcation (62 mm × 58 mm), so he underwent a percutaneous endovascular aortic repair (EVAR) on 24 May 2023, with no clinical and/or surgical complications and discharged with antiaggregant therapy. After the intervention, his renal function remained stable, but in September 2023, his serum creatinine was 3.5 mg/dL with an eGFR 18 mL/min/1.73 m² and started fluctuating, reaching a value of 4.4 mg/dL with an eGFR 14 mL/min/1.73 m² in October 2023 and then declining till 3.9 mg/dL with an eGFR 16 mL/min/1.73 m² on January 2024. Moreover, since October 2023, he has presented hyper eosinophilia (8.8%) and skin lesions at the lower extremities. At the admission to our hospital on February 2024 biochemical tests showed a further worsening of his renal function (serum creatinine 6 mg/dL and eGFR 9 mL/min/1.73 m²); increase of eosinophil count; thrombocytopenia; the abdominal ultrasound (US) showed the patency of the aorto-bisiliac prosthesis, in absence of endoleak, and with open renal arteries. The renal US with evaluation of renal resistance indices showed right kidney of reduced size (longitudinal diameter [LD] 58 mm, Resistance Indices [IR] 0.9), already known in his medical history; left kidney of normal size (LD 105 mm, RI 0.9). The combination of vascular surgery, subacute kidney function decline with increased renal resistance indices, skin lesions, and hyper eosinophilia was strongly suggestive of AEKD. Of note, an abdominal magnetic resonance imaging performed to better evaluate a complex haemorrhagic cyst localized to the left superior renal pole (already present long before vascular surgery), described multiple extended triangular regions in the spleen likely due to ischemic injuries caused by arterial emboli.

During the recovery, we observed the worsening of thrombocytopenia, anemia, despite the support therapy with erythropoietin, increased LDH; thus, we evaluated plasmatic haptoglobin which resulted reduced, the peripheral blood smear revealed the presence of some fragmented red cells and the ADAMTS13 was normal (see Table 1). The genetic evaluation, performed through next-generation sequencing (NGS), showed no mutations of the genes involved in complement activity.

These results led us to promptly diagnose an aHUS likely due to subacute AEKD. The patient immediately started treatment with ravulizumab, a more recent long-acting C5a inhibitor, combined to antimeningococcal vaccination and antimicrobial prophylaxis. Platelets, hemoglobin and LDH already improved after 14 days from ravulizumab loading dose, while renal function improved more gradually during the maintenance therapy till a serum creatinine of 2.8 mg/dL, eGFR 23 mL/min/1.73 m² before the 2th maintenance dose of ravulizumab, with no adverse effects (see Table 1). Currently, the patient is in good clinical conditions and he is going on maintenance therapy every 8 weeks without any adverse effects.

To our knowledge, this is the first case of aHUS secondary to a subacute AEKD. Even if surgical interventions can trigger the development of aHUS, in our case EVAR was performed too long ago to be considered responsible for the syndrome. In fact, after the EVAR the patient presented a period of stable renal function and only 4 months after the vascular surgery, the patient developed a decline of renal function combined to eosinophilia consistent with a subacute presentation of AEKD.

He came to our observation when he already presented the suspicious serum chemistry characteristics of aHUS: a reduction of the hemoglobin, platelet count, and a severe acute kidney injury, combined to hypereosinophilia and C3 consumption. Consequently, we measured serum haptoglobin, ADAMTS13 activity and the presence of fragmented red cells, which supported our diagnosis. We promptly started therapy with ravulizumab, which is a new C5 inhibitor with immediate and sustained effect across an extended, 8-week dosing interval. It was first introduced in 2018 as a therapeutic candidate for aHUS and approved in the USA in 2019, in the European Union in 2020, and on May 2023, it was approved by Italian Medicine Agency. Similarly to eculizumab which is its predecessor, ravulizumab binds to C5 and prevents its dissociation into C5a and C5b, thereby interrupting the complement cascade [3]. Ravulizumab presents the same efficacy and safety of eculizumab but a longer half-life because of its modified structure compared; this characteristic allows less frequent infusions, thus reducing treatment burden and improving patient’s quality of life. In particular, our patient presented an early hematological response after 15 days from ravulizumab initiation and a slower renal recovery, as expected by the so far available data; it is noteworthy that 15 days corresponds to platelet half-life and the hematological response to the therapy in this timeframe is a positive prognostic factor for the improvement of kidney function. In fact, recent findings showed that the normalization of the platelet count on days 8 and 15 of ravulizumab treatment was associated with the renal function recovery within the 26-week initial treatment period; moreover, the earlier is the platelet response, the earlier is the renal recovery during treatment with ravulizumab, as already showed with eculizumab [4]. In our case, we excluded a primary genetic form because no mutations in genes coding for proteins involved in the complement cascade or its regulation were found. Secondary forms are associated with triggering factors in the absence of mutations; no previous findings are available about AEKD as the etiological cause of aHUS. We hypothesized that the embolization of cholesterol crystals following the EVAR could have caused a subacute AEKD; the same cholesterol crystals likely led to an endothelial dysfunction with the activation of the complement cascade resulting in a secondary aHUS [5]. Moreover, the activation of complement system could be the pathophysiological common point connecting AEKD and aHUS; indeed, Cosio et al. [6] showed low serum complement levels in 7 patients with atheroembolic disease, without evidence of other clinical reasons for hypocomplementemia and in an experimental model of atheroembolic disease in rats they showed that the hypocomplementemia was the result of complement activation by the atheromatous material in vivo.

In conclusion, AEKD and aHUS could share the involvement of the complement system in their pathophysiological mechanism and the former could lead to the latter. Because AEKD and aHUS are rare and underdiagnosed, it is crucial to improve the awareness of physicians about these two conditions. Our case suggests the importance of a close monitoring after events which could potentially trigger these diseases in order to promptly recognize and treat them. Indeed, further studies are necessary to fill the gap in the knowledge of the precise mechanism leading to aHUS secondary to AEKD and to confirm that they are two sides of the same coin.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

I.C.: concept and design of the manuscript, acquisition of the data, interpretation of the data, draft of the article, final approval of the version to be published, and agreement to be accountable for all aspects of the work; P.B. and M.A.: acquisition of the data, interpretation of the data, revision of the manuscript, final approval of the version to be published, and agreement to be accountable for all aspects of the work; and E.R. and A.P.: interpretation of the data, revision of the manuscript, final approval of the version to be published, and agreement to be accountable for all aspects of the work.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.