Skip to main content

An autopsy case of a patient on maintenance hemodialysis with continuous idiopathic cholesterol crystal embolism for 7 years



CCE is a systemic disease with poor prognosis with no established treatment. Approximately 23–32% of CCE cases progress to end-stage renal failure, and the 1-year mortality rate of CCE with organ failure is 60–90%. The dialysis method for the patients with CCE is still controversial.

Case report

The patient is 73 years old male who was diagnosed with idiopathic CCE. He had survived 7 years though he had been on maintenance HD. We used nafamostat for HD every time. He took prednisolone and statin. He died due to rupture of AAA and we autopsied him. CCs developed in five organs, including the right lung CCE was assumed to be continuously present since the diagnosis.

Discussion and conclusion

CCE was continuous until death, and CCs in the right lung were possibly due to HD. HD through AV shunt could worsen CCE, and HD should be recognized as the aggravating factor. The use of nafamostat while undergoing HD as well as use of steroids and statins until death may have prevented fatal events and contributed to the patient's long survival.


CCE (Cholesterol crystal embolism) is a systemic disease with poor prognosis caused by formation of cholesterol crystal emboli in multiple organs. Approximately 23–32% of CCE cases progress to end-stage renal failure, and the 1-year mortality rate of CCE with organ failure is 60–90% [1]. In addition, at a mean follow-up of 5 years, end-stage renal disease and death have been reported to occur in 24% and 38% CCE cases, respectively [2]. There is no established treatment for CCE [3]. Idiopathic CCE occurs without endovascular manipulation, accounts for approximately 20% CCE cases, and is rare compared with iatrogenic CCE [2].

Case presentation

X-7 years 73 years old male was admitted to our hospital because of progressive renal failure. Two months before admission, he was diagnosed with atherosclerotic brain infarction and treated by oral antiplatelet therapy (100-mg aspirin daily). Since then, his creatinine level had worsened gradually for 2 months. Blue toe was noticed on his big left toe, and skin biopsy was taken. He was diagnosed with CCE as skin biopsy showed CC (Fig. 1). We stopped the administration of aspirin and prescribed 20-mg (0.33 mg/kg daily) oral prednisolone, but his renal failure had progressed. Maintenance hemodialysis (HD) was initiated one month after the diagnosis. Prednisolone was reduced to 10 mg (0.17 mg/kg) daily and we used nafamostat for HD every time. LDL-C (Low-density lipoprotein cholesterol) had been well controlled with atorvastatin. He was discharged after initiation of HD through artery and vein shunt (AV) shunt. He had been stable for 7 years since the initiation of HD. His condition was good enough, and he could come to our hospital all by himself to undergo maintenance HD. He received ESA (erythropoiesis stimulating agent) occasionally depends on Hemoglobin while HD. D-dimer had been continuously below 6 μg/mL, which did not suggest chronic disseminated intravascular coagulation. Eosinophil count had been under 500.

Fig. 1
figure 1

Cholesterol clefts in skin at the diagnosis 7 years before admission. CCs are surrounded with leukocytes without fibrosis, and these are the acute findings

X-1 year He became forgetful and Alzheimer’s disease was suspected.

X-16 days He had become agitated and irritated gradually and was admitted to our hospital for evaluation.

The patient was in an agitated state and had lost weight. He took 10-mg prednisolone (0.25 mg/kg) daily. Results of blood panel are shown in Table 1. CT(Computed tomography) and magnetic resonance imaging of the brain revealed no new cerebrovascular abnormality. Chest and abdominal CT showed aortic aneurysm. The maximum diameter of the aneurysm was 53.6 mm and 48.6 mm in the chest and abdominal aorta, respectively, which is not indicative of surgical treatment in elderly people. We considered Alzheimer’s disease as the most likely condition and initiated palliative care. On the seventh day, the patient developed blue toe syndrome on his right toe; however, we did not perform an additional skin biopsy as CCE was already diagnosed. On the 19th day, the patient demonstrated delayed responsiveness at 10 min after a stimulus of routine care by the nurse. Although we attempted resuscitation, he died. Results of the blood test conducted during resuscitation did not reveal the cause of death. D-dimer at the death was 20.3 µg/mL. Systemic CT after death revealed rupture of an aortic aneurysm, resulting in bleeding to the intraperitoneal area. An autopsy was performed.

Table 1 Results of blood panel on admission

His medical history included CCE, hypertension, atherothromboric cerebral infarction (7 years prior), gastric ulcer (5 years prior), compression infarction and severe drug eruption (3 years prior). He took oral prednisolone (10 mg), furosemide (120 mg), carvedilol (10 mg), sulfamethoxazole (800 mg), trimethoprim (160 mg), lansoprazole (30 mg), atorvastatin calcium hydrate (5 mg), febuxostat (5 mg), risperidone (1 mg), and Yokukansan (7.5 mg), which is a Chinese medicine, daily. He had been smoking 20 cigarettes per day until 7 years ago and he is occasional alcohol drinker.

Autopsy result

Autopsy was performed 9 h and 48 min after death. Findings revealed abdominal aortic aneurisms (AAA) from the inferior mesenteric artery level to the level of both common iliac arteries. Rupture of the aneurism on the left side of the lower mesenteric artery was considered to be the direct cause of death (Fig. 2). The aorta was found to have extensive atherosclerosis, from the thoracic aorta to the abdominal aorta, from which CCE seemed to develop (Fig. 3). CCs were occluded in multiple organs, including the right lung (Fig. 4), spleen (Fig. 5), kidneys (Fig. 6), adrenal gland (Fig. 7), and skin (Fig. 8). In the lungs, CCs were found in the right upper lobe, and not in the left lung. Atherosclerosis was not noted in the pulmonary arteries. We could not identify bronchial arteries owing to massive atherosclerosis in the aorta. Multinucleated histiocytes around CCs were observed in the lung (Fig. 4). CCs in the spleen (Fig. 5) and the kidneys (Fig. 6) were surrounded by leukocytes accompanied by fibrosis. These acute to subacute findings suggested that CCE had occurred even after the diagnosis. On the other hand, CCs in the adrenal gland (Fig. 7) were surrounded by fibrosis without leukocytes. Neovascular and granulation tissue are observed in the skin (Fig. 8). These findings suggested that considerable time had passed since CCs developed. The onset of CCE seems to be diverse and this suggests that CC has continued since diagnosis. Signs of a previous myocardial infarction were also found.

Fig. 2
figure 2

Rupture of aortic aneurism

Fig. 3
figure 3

Atherosclerosis of the aortic intima

Fig. 4
figure 4

CC in the right lung. Leucocytes infiltrate the region around CCs without fibrosis. Multinucleated histiocytes (red arrow) are observed around CCs

Fig. 5
figure 5

CC in the spleen. Leukocytes (blue arrow) infiltrate the region around CCs, but fibrosis (red arrow) around CCs is also observed

Fig. 6
figure 6

CC in the kidney surrounded with fibrosis and leukocytes

Fig. 7
figure 7

CC in the adrenal glands surrounded with fibrosis. These seem to be old findings

Fig. 8
figure 8

CC in the skin. Leukocytes infiltrate the region around CC. Neovascular (blue arrow) and granulation tissue (red arrow) are seen


Reportedly, end-stage renal disease and death occurred in 24% and 38% cases of CCE, respectively, at a mean follow-up of 5 years [2]. Irrespective of that, there exists no established treatment for CCE. Our patient survived for 7 years after the diagnosis of CCE even though he had end-stage renal failure and was undergoing HD.

CCE is divided into two types. Iatrogenic CCE that occurs following endovascular manipulation and anticoagulation therapy accounts for approximately 80% of CCE cases. Idiopathic CCE that occurs without the use of such maneuvers accounts for approximately 20% of cases [1]. Our patient underwent only antiplatelet therapy for atherosclerotic brain infarction; therefore, we diagnosed him with idiopathic CCE. We assumed this case as very rare not only because of idiopathic CCE but also because the patient survived long period of 7 years, owing to which we had performed an autopsy.

CCE develops following peripheral artery occlusion caused by needle-shaped cholesterol crystals that are detached from ruptured atheromatous plaques or fibrin microthrombi [4]. Fries et al. reported that of the 51 autopsies performed for CCE cases, 29 were found to have CCs in just one organ. The organs most affected were the kidneys (71%), spleen (37%), and lower gastrointestinal tract (22%). The lungs were affected to a lower extent (5.9%, the detail was not reported). Only one of the 51 cases had CCs in 5 organs, and all others had CCs in 2–4 organs [4]. In this study, CCs were found in five organs. CCE seems to have developed for 7 years until death, as acute to subacute CCs were found in the spleen and kidney. CCs can potentially travel via the systemic circulation through the bronchial arteries. Another way CCs can occur in the lungs could be via the pulmonary artery [5]. However, CCs in the lungs are distinctly uncommon in the absence of arteriovenous fistula [6]. Our literature search revealed only six cases with CCs in the lungs that were detected via autopsy or biopsy (Table2). Of these, four cases had AV shunt for HD [7,8,9,10]. In one case, CCE occurred after surgical repair of an abdominal aortic aneurysm tear with an aortocaval fistula [11]. In one case, the presence of AV shunt was not clearly manifested, although the patient was undergoing HD. The possibility of an AV shunt in any other organ like the liver or brain was discussed in a previous report [5]. In our study, CCs were found in the right upper lung lobe only, and there was no atherosclerosis in the pulmonary arteries. CCs in the right lung were assumed to have originated from aortic atherosclerosis through the AV shunt. Blood access other than AV shunt such as subcutaneously fixed superficial artery and peritoneal dialysis (PD) could be the first choice for such patients requiring dialysis to avoid fatal CC occlusion into lungs via the AV shunt [7, 12].

Table 2 6 cases CCs in the lungs were detected

Reportedly, CCE exacerbates with the use of an anticoagulation drug. Anticoagulation therapy itself could be the cause of iatrogenic CCE. Although only case reports have been reported regarding the dialysis method; moreover, it is still unclear as to which anticoagulation drugs are the best for HD. Few studies have reported on worsening of CCE following HD using heparin [7, 8, 13, 14]. Sugawara also reported the case of an outpatient undergoing HD who was stable for 5 years with the use of LMWH (low-molecular weight heparin) [14]. HD should be recognized as a factor that can exacerbate CCE, for which should be considered. PD, which avoids the use of an anticoagulation drug, could thus be the first choice for the patients requiring dialysis not to aggravate CCE [7]. In the present study, we used nafamostat for our patient, which appeared beneficial as we did not observe any fatal event, embolic shower, or bleeding.

There is no established treatment for CCE. Currently, there are no large trials evaluating therapies for treating patients with CCE. Regarding the mechanism of CCE, embolization of CCs causes ischemic injury, and the subsequent inflammatory reaction aggravates and perpetuates the injury [15]. Not only the CCs but also the fibrin clots forming around CCs obstruct the peripheral arteries, causing tissue infarction and organ failure [5]. Endothelial injury, complement activation, oxidative stress, activation of the renin–angiotensin–aldosterone system, leukocyte aggregation, and release of leukocyte enzymes are all considered responsible for end-organ injury. CCs cause inflammatory reactions around the arterioles resembling a foreign-body giant cell reaction. The complement pathway is also an important aspect of CCE [16]. Thus, anti-inflammatory agents such as steroids may be effective in CCE [17, 18]. However, recent reports have shown an effective improvement (Table3) [19,20,21,22,23]. The effectiveness, effective amount of steroid, and effective duration of prescription are still unknown. Similar to the patient in our study, a previous study reported that the patient survived 5 years while receiving 10 mg prednisolone daily. In addition, cessation of prednisolone aggravated skin symptoms and eosinophilia, for which prednisolone was initiated and continued [14]. In the present study, we had prescribed 20 mg prednisolone for a month and continued 10 mg prednisolone daily until patient death, and it seemed to benefit the patient as CCE did not aggravate until death even though CCE had occurred after the diagnosis. Recently colchicine or cyclophosphamide has been suggested to be effective. CCs activate the IL1β pathway via the NLRP3 inflammasome molecule and induce TNF and MIP2 secretion. This NLRP3/IL1 pathway in the pathogenesis of CCE was recently discovered, and the efficacy of IL1 antagonists (canakinumab) has been investigated [15].

Table 3 Steroid dosage that was effective in the case reports

Aortic atherosclerotic plaque is an important source of CCE. A study reported that among 519 patients with thoracic aortic atherosclerotic plaques, 1% had CCE at > 3 years [24]. When idiopathic CCE is diagnosed, the presence of aortic plaque should be investigated as it could be the source of CCE. Older age, male sex, smoking, heart failure, peripheral vascular disease, cerebrovascular disease, renal insufficiency, DM(Diabetes Mellitus), hypertension, and aortic aneurism and dissection have been significantly associated with a higher frequency of CCE [4, 25], and these are also the well-known factors of atherosclerotic plaque. We believe that controlling these factors is considerably important to prevent and manage both atherosclerosis and CCE. We could not find the direct relation between CCE, its prognosis and DM but DM is definitely a strong risk factor of CCE. Takahashi et al. [26] report that 40% of CCE patient had DM. Anemia could be caused by CCE [15]. However, Hb level of maintenance HD patient is well controlled by ESA like this patient. Statins may provide primary beneficial effects against CCE by lowering LDL-C levels, stabilizing atherosclerotic plaques, and mediating pleiotropic anti-inflammatory effects [15]. Scolari reported that baseline treatment of LDL-C reduced the risk of end-stage renal disease and improved 1-year cumulative survival [2]. Tunick reported that statin reduces the ratio of embolic event from thoracic aortic plaque with an odds ratio of 0.3 [24]. LDL-C apheresis is also a choice for treatment [27]. This patient had extensive atherosclerosis from the thoracic aorta to abdominal aorta, from which CCE seemed to develop. LDL-C was well controlled with statins, and the patient discontinued smoking after diagnosis.

In summary, we report an autopsy case of a patient undergoing maintenance HD who developed idiopathic CCE and survived for 7 years. CCE was supposed to be continuous since the diagnosis and develop into five organs over 7 years. CCs in the right lung might have developed via HD through the AV shunt. The use of nafamostat while undergoing HD could prevent a fatal event. Prednisolone 10 mg daily might help in controlling inflammation caused by CCE. Aortic atherosclerotic plaque is an important source of CCE, and statins could help stabilize atherosclerotic plaques. Nafamostat, steroids, and statins could prevent fatal events and contribute to long survival.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.



Cholesterol crystal embolism




Aortic abdominal aneurism

AV shunt:

Artery and vein shunt


Low-density lipoprotein cholesterol


Computed tomography


Low-molecular weight heparin


Diabetes mellitus


Erythropoiesis stimulating agent


  1. Scolari F, Tardanico R, Zani R, Pola A, Viola BF, Movilli E, et al. Cholesterol crystal embolism: a recognizable cause of renal disease. Am J Kidney Dis. 2000;36(6):1089–109.

    Article  CAS  PubMed  Google Scholar 

  2. Scolari F, Ravani P, Pola A, Guerini S, Zubani R, Movilli E, et al. Predictors of renal and patient outcomes in atheroembolic renal disease: a prospective study. J Am Soc Nephrol. 2003;14(6):1584–90.

    Article  PubMed  Google Scholar 

  3. Masuda J, Tanigawa T, Nakamori S, Sawai T, Murata T, Ishikawa E, et al. Use of corticosteroids in the treatment of cholesterol crystal embolism after cardiac catheterization: a report of four Japanese cases. Intern Med. 2013;52(9):993–8.

    Article  CAS  PubMed  Google Scholar 

  4. Fries C, Roos M, Gaspert A, Vogt P, Salomon F, Wüthrich RP, et al. Atheroembolic disease–a frequently missed diagnosis: results of a 12-year matched-pair autopsy study. Medicine. 2010;89(2):126–32.

    Article  PubMed  Google Scholar 

  5. Sabatine MS, Oelberg DA, Mark EJ, Kanarek D. Pulmonary cholesterol crystal embolization. Chest. 1997;112(6):1687–92.

    Article  CAS  PubMed  Google Scholar 

  6. Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: a review of 221 cases in the English literature. Angiology. 1987;38(10):769–84.

    Article  CAS  PubMed  Google Scholar 

  7. Amari Y, Inoue K, Matsuo S, Nishihara G, Nakano R. An autopsy case showing spontaneous choresterol crystal embolization in multiple organs following renal failure. J Jpn Soc Dial Ther. 2010;43(1):87–92.

    Article  Google Scholar 

  8. Nakakoji Y, Ishiguro H, Kusakawa Y, Kawashima T, Takizawa T, Omatsu M, et al. An autopsy case of pulmonary embolism after hemodialysis was initiated because of cholesterol crystal embolization. Nihon Toseki Igakkai Zasshi. 2011;45:79–85.

    Article  Google Scholar 

  9. Kono Y, Takizawa H, Yamaji I, Takada T, Shinohara T, Tanaka S, et al. Pulmonary atheroembolism via an AV shunt. J Vasc Access. 2006;7(3):139–42.

    Article  CAS  PubMed  Google Scholar 

  10. Kojima M, Sugiyama K, Hasegawa M, Kiriyama Y, Kuroda M, Hasegawa Y. An autopsy case of spontaneous cholesterol embolism. Ther Res. 2012;33(8):1176–7.

    Google Scholar 

  11. Weigent CE. Pulmonary atheroembolism complicating repair of an atherosclerotic abdominal aneurysm. Minn Med. 1978;61:15–6.

    CAS  PubMed  Google Scholar 

  12. Siemons L, van den Heuvel P, Parizel G, Buyssens N, De Broe ME, Cuykens JJ. Peritoneal dialysis in acute renal failure due to cholesterol embolization: two cases of recovery of renal function and extended survival. Clin Nephrol. 1987;28(4):205–8.

    CAS  PubMed  Google Scholar 

  13. Kakeshita K, Koike T, Imamura T, Arisawa Y, Murai S, Shimizu A, et al. Cholesterol embolization syndrome and intra-abdominal bleeding immediately after initiation of hemodialysis: a case report with literature review. Ren Replace Ther. 2020;6(1):53.

    Article  Google Scholar 

  14. Sugawara K, Takeda K, Miura S, Fukuda T, Tobino K, Wakasugi D. A case of choresterol embolism (CE) with end-stage renal disease who was able to continue stable out patient hemodialysis for about five years. J Jpn Soc Dial Ther. 2007;40(2):183–8.

    Article  Google Scholar 

  15. Ozkok A. Cholesterol-embolization syndrome: current perspectives. Vasc Health Risk Manag. 2019;15:209–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shi C, Kim T, Steiger S, Mulay SR, Klinkhammer BM, Bauerle T, et al. Crystal clots as therapeutic target in cholesterol crystal embolism. Circ Res. 2020;126(8):e37–52.

    Article  CAS  PubMed  Google Scholar 

  17. Wongprasartsuk S, Finlay M, Perry GJ. Cholesterol emboli to the kidney: an immunoperoxidase study. Pathology. 2001;33(2):157–62.

    Article  CAS  PubMed  Google Scholar 

  18. Higo S, Hirama A, Ueda K, Mii A, Kaneko T, Utsumi K, et al. A patient with idiopathic cholesterol crystal embolization: effectiveness of early detection and treatment. J Nippon Med Sch. 2011;78(4):252–6.

    Article  PubMed  Google Scholar 

  19. Nakayama M, Nagata M, Hirano T, Sugai K, Katafuchi R, Imayama S, et al. Low-dose prednisolone ameliorates acute renal failure caused by cholesterol crystal embolism. Clin Nephrol. 2006;66(4):232–9.

    Article  CAS  PubMed  Google Scholar 

  20. Boero R, Pignataro A, Rollino C, Quarello F. Do corticosteroids improve survival in acute renal failure due to cholesterol atheroembolism? Nephrol Dial Transplant. 2000;15(3):441–441.

    Article  CAS  PubMed  Google Scholar 

  21. Koga J, Ohno M, Okamoto K, Nakasuga K, Ito H, Nagafuji K, et al. Cholesterol embolization treated with corticosteroids–two case reports. Angiology. 2005;56(4):497–501.

    Article  PubMed  Google Scholar 

  22. Mann SJ, Sos TA. Treatment of atheroembolization with corticosteroids. Am J Hypertens. 2001;14(8 Pt 1):831–4.

    Article  CAS  PubMed  Google Scholar 

  23. Fabbian F, Catalano C, Lambertini D, Bordin V, Di Landro D. A possible role of corticosteroids in cholesterol crystal embolization. Nephron. 1999;83(2):189–90.

    Article  CAS  PubMed  Google Scholar 

  24. Tunick PA, Nayar AC, Goodkin GM, Mirchandani S, Francescone S, Rosenzweig BP, et al. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol. 2002;90(12):1320–5.

    Article  PubMed  Google Scholar 

  25. Tanaka H, Yamana H, Matsui H, Fushimi K, Yasunaga H. Proportion and risk factors of cholesterol crystal embolization after cardiovascular procedures: a retrospective national database study. Heart Vessels. 2020;35(9):1250–5.

    Article  PubMed  Google Scholar 

  26. Takahashi K, Omuro A, Ohya M, Kubo S, Tada T, Tanaka H, et al. Incidence, risk factors, and prognosis of cholesterol crystal embolism because of percutaneous coronary intervention. Am J Cardiol. 2022;167:15–9.

    Article  CAS  PubMed  Google Scholar 

  27. Daimon S, Motita R, Ohtsuki N, Chikaki H, Jigen K, Koni I. LDL apheresis followed by corticosteroid therapy as a possible treatment of cholesterol crystal embolism. Clin Exp Nephrol. 2000;4(4):352–5.

    Article  Google Scholar 

Download references


Not applicable


Not applicable.

Author information

Authors and Affiliations



Not applicable.

Corresponding author

Correspondence to Yumiko Kawai.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Informed consent was obtained from all individual participants included in the study.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawai, Y., Kinoshita, C., Matsuda, K. et al. An autopsy case of a patient on maintenance hemodialysis with continuous idiopathic cholesterol crystal embolism for 7 years. Ren Replace Ther 9, 22 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: