|Year : 2018 | Volume
| Issue : 1 | Page : 18-23
Deterioration of renal function is associated with increased mortality in patients with cholesterol crystal embolism
Akihito Tanaka, Yu Watanabe, Takahiro Mizukawa, Hibiki Shinjo, Kiyomi Koike, Yasuhiro Otsuka, Asami Takeda
Kidney Disease Center, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
|Date of Web Publication||26-Mar-2018|
Dr. Akihito Tanaka
Japanese Red Cross Nagoya Daini Hospital, 2-9, Myoken-cho, Showa-Ku 466-8650, Nagoya
Source of Support: None, Conflict of Interest: None
Background and Objectives: The importance of arteriosclerotic diseases has increased in recent years owing to population aging. Increased in the incidence of catheter intervention and vascular surgery has also resulted in a corresponding increase of cholesterol crystal embolism (CCE). Patients with chronic kidney disease are often diagnosed with arteriosclerotic disease. Although the severity of CCE varies widely, because it exacerbates renal function, treatment options should be established based on CCE severity. Methods: In this retrospective study, we examined 43 patients (37 men and 6 women; mean age, 74.9 ± 7.2 years) who were admitted to our department from 2002 to 2017 because of deteriorating renal functions. We assessed these patients at admission and followed up 1-year later. Results: The causes of CCE included treatment for ischemic heart disease (41.9%), aortic aneurysm (23.3%), and the administration of warfarin (11.6%). Thirty-one patients (72.1%) were diagnosed pathologically. The mean level of creatinine (Cr) at baseline was 1.84 ± 0.83 mg/dL. The mean level of Cr on admission was 4.90 ± 2.2 mg/dL. Steroid therapy was performed in 27 patients (62.8%) and lipoprotein apheresis was performed in one patient (2.3%). During the observational period, 9 patients (20.9%) died and the increase in Cr rates was significantly higher in these individuals (P = 0.0044). After adjustment for various factors, the Cr increase rate was significantly related to mortality (hazard ratio: 2.9581, 95% confidence interval: 1.1179–7.8271, P = 0.0289). Conclusion: The deterioration rate of renal function is associated with mortality in patients with CCE, which is accompanied by renal manifestation.
Keywords: Cholesterol crystal embolism, chronic kidney disease, creatinine, mortality
|How to cite this article:|
Tanaka A, Watanabe Y, Mizukawa T, Shinjo H, Koike K, Otsuka Y, Takeda A. Deterioration of renal function is associated with increased mortality in patients with cholesterol crystal embolism. J Integr Nephrol Androl 2018;5:18-23
|How to cite this URL:|
Tanaka A, Watanabe Y, Mizukawa T, Shinjo H, Koike K, Otsuka Y, Takeda A. Deterioration of renal function is associated with increased mortality in patients with cholesterol crystal embolism. J Integr Nephrol Androl [serial online] 2018 [cited 2018 Dec 16];5:18-23. Available from: http://www.journal-ina.com/text.asp?2018/5/1/18/228495
| Introduction|| |
In recent years, the importance of arteriosclerotic diseases has increased in response to the increased number of the aging population. The occurrence of cholesterol crystal embolism (CCE) has increased along with the higher incidence of catheter intervention and vascular surgery. CCE is a multisystemic disease caused by the occlusion of small arteries by cholesterol crystal emboli derived from ulcerated atherosclerotic plaques.,, As a multi-systemic disease, CCE involves many organs, including the kidneys, skin, gastrointestinal tract, eyes, muscle, and central nervous system.,, CCE results in the deterioration of renal function in chronic kidney disease (CKD) and patients with CKD often develop atherosclerotic diseases. Patients with CCE are reported to have a poor prognosis because they are often complicated with the cardiovascular events., The severity of CCE can vary widely, from a mild case of skin lesions without renal deterioration to a severe case with rapidly progressive kidney dysfunction. Various treatment options can be performed such as avoiding inducible factors, steroid therapy, statins, and low-density lipoprotein apheresis (LDL-A);,, however, the classification in regard to the severity of cases and it is not established which patients should be treated intensively. We thought that treatment with high intensity should be performed for cases with high severity and high probability of death, and it was necessary to select cases with high severity first. Hence, we aimed to find CCE cases with high severity. We hypothesize that patients with high degree of deterioration of renal function have severe organ dysfunction and resulted in a high probability of death, and decided to assess it. In this study, we examined patients admitted to our department due to deteriorating renal functioning, and assessed their characteristics, treatment, and prognosis. We then explored the factors that were associated with the risk of mortality.
| Methods|| |
Patients and data collection
This was a retrospective study examining 43 patients with CCE who were admitted to our department because of exacerbation of renal function from April 2002 to May 2017. This study was approved by the Ethical Committee of the Institutional Review Board of the Japanese Red Cross Nagoya Daini Hospital and was conducted following the practices of the Declaration of Helsinki.
We collected the patients' data, including their medical history, physical examination results, laboratory test results, and medications, from a medical record review. CCE was diagnosed histologically or clinically. The term “cardiovascular disease events (CVDs)” included ischemic heart disease, heart failure, stroke, peripheral artery disease, and aortic disease. Baseline kidney function was clinically adopted before deterioration began and clearly differed from the transition of renal function until then. Estimated glomerular filtration rate (eGFR) was calculated from the formula for the Japanese population. Most of the baseline eGFR values were obtained just before cardiac surgery or catheter intervention. The primary outcome is defined as death. We followed up for 1 year and assessed mortality; patients who had died within that time were defined as the dead group (Group D), and those still alive as the living group (Group A). We compared the clinical characteristics, physical findings, laboratory data, and treatment between both groups.
Baseline characteristics were presented descriptively and were tested using the Mann–Whitney U-test and the Chi-square test. Survival was analyzed using uni- and multivariate Cox regression analysis. The hazard ratio (HR) was represented graphically using forest plots. Receiver operative characteristic (ROC) curves were used to evaluate the percentage of creatinine (Cr) increase that could detect death. P < 0.05 was considered statistically significant.
| Results|| |
Of the 43 patients included in the study, 37 were male and 6 were female (mean age, 74.6 ± 7.2 years). The causes of CCE were the examination or treatment of ischemic heart diseases (n = 18, 41.9%), aortic aneurysm (n = 10, 23.3%), warfarin administration (n = 5, 11.6%), intervention for arteriosclerosis obliterans (n = 4, 9.3%), carotid endarterectomy (n = 1, 2.3%), and percutaneous transluminal renal angioplasty (n = 1, 2.3%). Of the patients, 31 (72.1%) were diagnosed pathologically; a skin biopsy was performed in 28 patients (65.1%), a kidney biopsy was performed in 2 patients (4.7%), and a carotid artery biopsy during a carotid endarterectomy was performed in 1 patient (2.3%). Since the patients were admitted to the department of nephrology, all patients showed deterioration of renal function, 37 (86.1%) of whom had skin symptoms. Many of the patients had been diagnosed with CKD; 21 patients (48.8%) had nephrosclerosis, 1 patient had membranous nephropathy (2.3%), 1 patient had focal segmental glomerulosclerosis (2.3%), and 13 patients had unknown causes (30.2%). There were seven patients (16.3%) who had not been previously diagnosed with CKD and CCE was thought to be the cause of the deterioration in renal function. The baseline level of Cr was 1.84 ± 0.834 mg/dL (median 1.70, interquartile range [IQR] 1.308–1.955). On admission, the Cr level was 4.90 ± 2.186 mg/dL (median 4.59, IQR 3.283–6.025). Antiplatelet agents were used in 29 patients (67.4%), anticoagulants in 12 (27.9%), and statins in 22 (51.2%) patients. After admission, the anticoagulants were discontinued. Steroid therapy was performed in 27 (62.8%) patients and LDL-A in 1 patient (2.3%). At the 1-year follow-up, 9 patients (20.9%) had died. The causes of death were infections (n = 2, 4.7%), CVDs (n = 2, 4.7%), malignancy (n = 1, 2.3%), and unknown (n = 4, 9.3%). [Table 1] shows the patient background and data at the time of admission for Group D (dead) and Group A (alive). Group D was significantly older (81 [76–83] vs. 75 [68.25–78] years old, P = 0.0204). Statins, antiplatelet agent, and anticoagulant administration rates tended to be higher in Group A, but no significant differences were observed. The duration from the CVDs to the onset tended to be shorter in Group D, but there was no significant difference. In Group D, the hemoglobin level was significantly lower (8.80 [8.30–9.43] vs. 10.60 [9.60–11.60] g/dL, P = 0.0086), and the Cr level was significantly higher (5.94 [4.81–8.62] vs. 4.22 [2.97–5.36] mg/dL, P = 0.0071). There was no difference between the levels of Cr at baseline between groups. The rate of Cr increase was significantly higher in Group D compared to Group A (2.93 [2.36–3.39] vs. 1.46 [0.96–2.01], 102%, P = 0.0044). Regarding patients who were not orally administered with statins at the time of admission, there was a greater tendency in Group A for additional administration until discharge, but no significant difference was observed. There was no difference in the steroid treatment rate, and LDL-A was performed in only one case.
Association of mortality and creatinine increase percentage
[Table 1] shows the characteristics of both groups. In Group D, there was a tendency for patients to be hospitalized early from suspected causes, although there was no significant difference. In addition, the Cr increase rate on hospital admission was significantly higher in Group D; therefore, we assumed that the Cr rise ratio represented severity and examined the HR using the Cr increase rate as an explanatory variable [Figure 1]. Even after adjustment with various factors, the greater the rate of Cr increase from baseline, the higher the related mortality rate. Furthermore, we examined the ROC curve of the Cr increase rate against the mortality rate [Figure 2], and the Cr increase rate of 261.5% was selected as the cutoff value. If the Cr increase rate is higher than this cutoff, we considered the patient to have a high mortality rate.
|Figure 1: Forest plot of the percentage change of Cr, which presents the HRs for mortality. Cr: Creatinine. HR: Hazard ratio. CI: Confidence interval. DM: Diabetes mellitus. Hb: Hemoglobin. Na: Sodium|
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|Figure 2: ROC curve of the percentage change of Cr for an increased risk of mortality. ROC: Receiver operator characteristic. AUC: Area under the curve. Cr: Creatinine|
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| Discussion|| |
We examined the prognostic factors of patients who were hospitalized due to CCE by comparing the patients who survived to those who had died. As a result, we found that a high rate of Cr increase was a poor prognostic factor for these patients. Therefore, considering the higher mortality rates of patients with a high Cr increase, we suggest that more aggressive treatment being considered for these patients. No significant differences were observed between the groups in regard to the treatments performed, such as steroid therapy and its dosage. Since there was only one LDL-A case, it was difficult to conclude in regard to its efficacy. For the statin treatment, although there were no significant differences, the rate of additional administration was higher in Group A patients who were not using statins; therefore, it could be considered an option for patients have not been subjected to this therapy.
CCE causes disorders in various organs, including the kidneys. However, it has been suggested that diagnosis cannot be confirmed because of a lack of a specific diagnostic marker, which has resulted in CCE often being overlooked. It is reported that CCE develops in 1.4% of patients after cardiac catheterization, and 64% of the patients with CCE develop renal impairment. It has also been reported that CCE occurs in 7% of patients with acute renal injury. Avoidance of catheter manipulation and anticoagulant therapy is important, if possible. Although the proportion of CCE varies depending on the surveyed population, a report has reported that CCE occurred in approximately 4% of hospitalized patients. In addition, the onset of kidney disorders varies between individuals (i.e., asymptomatic in some cases, slow progression to either acute or subacute stages)., In our study, we targeted patients who had been hospitalized in the Department of Nephrology, and thus who had a relatively rapid deterioration of renal function and robust kidney symptoms. Furthermore, our study indicated an inverse correlation between the decline in patient prognosis and elevation of the Cr increase rates; the patients included in this study were considered to be severe cases based on these results. In a previous report, patients who had reached end-stage renal disease were reported to have a poor prognosis. In this study, it was considered that the prognosis was poor if the Cr increase rate was large, even when dialysis was not required. Aggressive treatment may be desirable for patients with a high Cr increase rate, but it is not precisely established which treatment should be aggressively applied. For each case, although steroid therapy, statin, and LDL-A were performed, we were unable to establish which treatment should be performed depending on the severity of the patient. While steroid therapy often demonstrates efficacy in short-term periods, it itself may disturb the blood pressure and blood glucose levels, and induce arteriosclerosis. There is also the risk of infection. Therefore, the steroid dosage and treatment period still need to be established, and the effects discussed.,,,, With regard to statins, if there is no adverse effect, it may be administered, enabling plaque stabilization. LDL-A is sometimes performed in severe cases and its efficacy has been reported., Severe cases were also included in this study, and there is a possibility that LDL-A would have been appropriate in some of these cases.
It is postulated that the treatment for CCE has yet to be established because of the wide variation in the severity of this condition, where some cases do not require aggressive treatment, while others cannot be rescued despite implementation of intensive treatment. Therefore, it is important to select patients who require aggressive treatment. This study is important in the sense that it provides information for that purpose. Our results showed that severity of renal dysfunction in patients with CCE was associated with mortality. Hence, we have to take care of these patients and treat them with high intensity.
This study has some limitations. First, it is a study in single center. Second, it is a retrospective study. The treatment policy is decided based on the judgment of the attending physician; therefore, the contents of treatment were not unified for each case.
| Conclusion|| |
The deterioration rate of a renal function is associated with mortality in patients with CCE, which is accompanied by renal manifestation.
We would like to thank Editage (www.editage.jp) for English language editing.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: A review of 221 cases in the English literature. Angiology 1987;38:769-84.
Thadhani RI, Camargo CA Jr., Xavier RJ, Fang LS, Bazari H. Atheroembolic renal failure after invasive procedures. Natural history based on 52 histologically proven cases. Medicine (Baltimore) 1995;74:350-8.
Mayo RR, Swartz RD. Redefining the incidence of clinically detectable atheroembolism. Am J Med 1996;100:524-9.
Saric M, Kronzon I. Cholesterol embolization syndrome. Curr Opin Cardiol 2011;26:472-9.
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;36:1089-109.
Modi KS, Rao VK. Atheroembolic renal disease. J Am Soc Nephrol 2001;12:1781-7.
Faria B, Vidinha J, Pêgo C, Garrido J, Lemos S, Lima C, et al
. Atheroembolic renal disease with rapid progression and fatal outcome. Clin Exp Nephrol 2011;15:159-63.
Dahlberg PJ, Frecentese DF, Cogbill TH. Cholesterol embolism: Experience with 22 histologically proven cases. Surgery 1989;105:737-46.
Li X, Bayliss G, Zhuang S. Cholesterol crystal embolism and chronic kidney disease. Int J Mol Sci 2017;18.
Desai M, Ram R, Prayaga A, Dakshinamurty KV. Cholesterol crystal embolization (CCE): Improvement of renal function with high-dose corticosteroid treatment. Saudi J Kidney Dis Transpl 2011;22:327-30.
] [Full text]
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;14:1584-90.
Ishiyama K, Sato T, Taguma Y. Low-density lipoprotein apheresis ameliorates renal prognosis of cholesterol crystal embolism. Ther Apher Dial 2015;19:355-60.
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al
. Revised equations for estimated GFR from serum creatinine in japan. Am J Kidney Dis 2009;53:982-92.
Quinones A, Saric M. The cholesterol emboli syndrome in atherosclerosis. Curr Atheroscler Rep 2013;15:315.
Fukumoto Y, Tsutsui H, Tsuchihashi M, Masumoto A, Takeshita A, Cholesterol Embolism Study (CHEST) Investigators. et al
. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: A prospective study. J Am Coll Cardiol 2003;42:211-6.
Haas M, Spargo BH, Wit EJ, Meehan SM. Etiologies and outcome of acute renal insufficiency in older adults: A renal biopsy study of 259 cases. Am J Kidney Dis 2000;35:433-47.
Scolari F, Ravani P, Gaggi R, Santostefano M, Rollino C, Stabellini N, et al
. The challenge of diagnosing atheroembolic renal disease: Clinical features and prognostic factors. Circulation 2007;116:298-304.
Meyrier A. Cholesterol crystal embolism: Diagnosis and treatment. Kidney Int 2006;69:1308-12.
Fabbian F, Catalano C, Lambertini D, Bordin V, Di Landro D. A possible role of corticosteroids in cholesterol crystal embolization. Nephron 1999;83:189-90.
Kronzon I, Tunick PA. Aortic atherosclerotic disease and stroke. Circulation 2006;114:63-75.
Mann SJ, Sos TA. Treatment of atheroembolization with corticosteroids. Am J Hypertens 2001;14:831-4.
Nakayama M, Izumaru K, Nagata M, Ikeda H, Nishida K, Hasegawa E, et al
. The effect of low-dose corticosteroids on short- and long-term renal outcome in patients with cholesterol crystal embolism. Ren Fail 2011;33:298-306.
Abela GS, Vedre A, Janoudi A, Huang R, Durga S, Tamhane U, et al
. Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am J Cardiol 2011;107:1710-7.
Vogt A. Hyperlipoproteinaemia(a)-apheresis and emerging therapies. Clin Res Cardiol Suppl 2017;12:12-7.
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