The protective role of coenzyme Q10 in renal injury associated with extracorporeal shockwave lithotripsy: a randomised, placebo-controlled clinical trial

Authors

  • Julia Carrasco,

    Corresponding author
    1. Department of Urology, Reina Sofia University Hospital, Cordoba, Spain
    • Correspondence: Julia Carrasco, Department of Urology, Reina Sofia University Hospital, Avda. Menendez Pidal s/n, CP: 14004, Cordoba, Spain.

      e-mail: juliacv83@hotmail.com

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  • Francisco J. Anglada,

    1. Department of Urology, Reina Sofia University Hospital, Cordoba, Spain
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  • Juan P. Campos,

    1. Department of Urology, Reina Sofia University Hospital, Cordoba, Spain
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  • Jordi Muntané,

    1. Department of General Surgery, Virgen del Rocio University Hospital/IBiS/CSIC/University of Seville, Seville, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD o Ciberehd), Instituto de Salud Carlos III, Madrid, Spain
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  • Maria J. Requena,

    1. Department of Urology, Reina Sofia University Hospital, Cordoba, Spain
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  • Javier Padillo

    1. Department of General Surgery, Virgen del Rocio University Hospital/IBiS/CSIC/University of Seville, Seville, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD o Ciberehd), Instituto de Salud Carlos III, Madrid, Spain
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  • These results are protected by a patent at the Spanish Office of Patents and Trademarks (Reference: P201131992)

Abstract

Objective

  • To determine the efficacy of coenzyme Q10 (CoQ10) in preventing renal injury in patients with lithiasis undergoing extracorporeal shockwave lithotripsy (ESWL).

Patients and Methods

  • Prospective, randomised, double-blind, placebo-controlled clinical trial of 100 patients with renal lithiasis who were treated with ESWL.
  • The patients were distributed randomly into two groups receiving either placebo or CoQ10 (200 mg/day), a powerful antioxidant with vasoactive properties, orally administered during the week before ESWL and for 1 week after.
  • Renal dysfunction markers, vasoactive hormones, oxidative stress, plasma levels of several interleukins and vascular resistance index (VRI) using Doppler ultrasound were evaluated the week before ESWL, 2 h before ESWL and at 2 h, 24 h and 7 days after ESWL.

Results

  • There was a significant increase in glomerular filtration (P = 0.013), as well as a decrease in the albumin/creatinine ratio and the β2-microglobulin level (P = 0.02) after 1 week of treatment in the CoQ10 group. These changes were maintained at the follow-up after ESWL.
  • The administration of CoQ10 was associated with improvement in vasoactive hormone parameters, VRI and interleukin levels. These improvements were maintained until the end of the follow-up period.
  • However, the administration of CoQ10 was not associated with significant changes in the oxidative stress parameters.

Conclusion

  • Our results indicate that CoQ10 administration improves renal function and vasoactive and inflammation parameter values, allowing for preconditioning before the tissue insult caused by ESWL.

Introduction

Urolithiasis is a very prevalent disease (1–15%), although its rate varies according to geographic area, climate and diet [1]. Extracorporeal shockwave lithotripsy (ESWL), which produces fragmentation of the calculi using shockwaves and facilitates calculi elimination through the excretory pathway, is currently the initial treatment of choice for uncomplicated kidney stones of <2 cm in diameter located in the upper urinary tract [2].

However, the action of the sound waves on the kidney causes damage to the renal parenchyma [3, 4]. The mechanisms underlying this damage are not well defined. The onset of inflammatory phenomena, imbalances in hormone regulation, such as the angiotensin II axis and oxidative stress with an increase of lipid peroxidation and a decrease in cellular antioxidant status, have been proposed as the underlying pathogenic mechanisms of the observed renal parenchymal damage [5, 6].

Coenzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is a lipid-soluble vitamin-like substance that is found in the membranes of many organelles, especially the inner membrane of mitochondria. This molecule participates in aerobic cellular respiration as an electron carrier for generating energy in the form of adenosine triphosphate in vivo [7]. In addition, CoQ10 has been shown to be a powerful antioxidant and regulator of vasoactive mechanisms in multiple studies on the prevention and treatment of cardiovascular disease, diabetes and renal diseases [8-10]. Nevertheless, CoQ10 has not been approved yet for therapeutic purposes by the USA Food and Drug Administration but is accepted as dietary supplement.

As there are no published clinical studies that have evaluated the effect of this ubiquinone to lessen renal damage in patients with lithiasis who undergo ESWL, thus we investigated the potential protective effects of CoQ10 against lithotripsy induced impairment of renal function.

Patients and Methods

A prospective, randomised, double-blind placebo-controlled study including 100 patients with renal lithiasis treated with ESWL was conducted at the University Hospital Reina Sofia in Cordoba (Spain) between April 2009 and December 2010. Institutional Review Board approval was obtained for this study registered on Current Controlled Trials (ISRCT N05823740). Informed written consent to participate in the study was obtained from all patients.

Inclusion Criteria

Adult patients with radio-opaque calculi ≤2 cm located in the renal pelvis and/or calyces with normal kidney function (creatinine <1.2 mg/dL) and blood pressure within the normal range (<130/90). Stone size was assessed by abdominal CT.

Exclusion Criteria

Patients with acute or chronic pathology that could alter the markers being studied (previous renal failure, hypertension, diabetes, cardiac pathology), as well as complete distal obstruction to the treated calculus, UTI or patients with a history of renal surgery or previous ESWL or other manipulation of the urinary tract, e.g. ureteroscopic lithotripsy, were also excluded.

Sample Size Study

For the estimation of the sample size, a study based on the efficacy of antioxidants in renal protection in patients with urolithiasis treated with ESWL was used [11]. Considering the methodological similarities between that study and ours, assuming an α error of 5% and a power of 90% with a maximum percentage of subjects lost during follow-up of 15–20%, the required number of patients was 98 patients (49 in each group). A P < 0.05 was considered to indicate statistical significance.

Study Design

Initially, 112 subjects were evaluated, and 12 patients were excluded (Fig. 1), leaving 100 subjects in the study (51 men and 49 women). The mean (sd) age was 48.27 (12.9) years.

Figure 1.

Study flow chart.

Patients were randomly assigned in a 1:1 ratio to receive CoQ10 or placebo. The sequence of randomisation was computer generated and was performed by the hospital's pharmacy service, whoever administered CoQ10 and placebo as capsules of the same type in identical bottles. The patient, the attending urologist, and the investigators were not aware of study arm assignments until the final assessment of outcome (Fig. 1).

Samples (blood and urine) were collected from all patients according to the following schedule:

  • Baseline determination: was done before administration of CoQ10 or placebo, the week before ESWL.
  • Before ESWL determination: was done 2 h before ESWL.
  • After ESWL: were done 2 h, 24 h and 7 days after ESWL.

Vascular resistance index (VRI) values were assessed using eco-Doppler ultrasound 7 days before ESWL as well as 24 h and 7 days after ESWL.

Treatment

The lithotripter used was an electromagnetic Dornier Compact Delta. The patients received a number of waves oscillated between 2000 and 3000. The intensity of the shockwave was scaled in relation to patient tolerance. All treatments reached a maximum wave intensity of 52 mJ and a frequency of 60 waves/min.

Due to the fact that after ESWL a fragmented stone can obstruct the ureter, which could alter the markers being studied, ultrasonography was used to confirm that there were no patients with complete obstruction.

CoQ10 or placebo was administered orally during the week before ESWL and for 1 week after. CoQ10 dosage was 200 mg/day as per previous studies [12, 13]. There were no adverse reactions to CoQ10.

Measurements

Blood samples (15–20 mL) were collected 8 h after fasting except for the samples collected at 2 h after ESWL. Urine was obtained earlier in the morning, representing a urinary excretion period of 6–8 h, with the exception of the sample collected 2 h after ESWL. Different plasma aliquots were frozen at –70 °C until they were analysed.

The markers of renal injury examined were estimated GFR using Modification of Diet in Renal Disease (MDRD) formula, as well as the albumin/creatinine ratio in urine and β2-microglobulin level in serum. Different vasoactive-related markers, e.g. rennin concentration, aldosterone concentration, and VRI were also determined. The levels of lipoperoxides (LPO), superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced Glutathione (GSH), and interleukin-1 (IL-1) and IL-6, related to oxidative stress and inflammatory response, respectively, were also determined in serum.

Biochemical measurements were performed via molecular spectrophotometry using the ARCHITECT c16000 analyser (Abbott Diagnostics, USA). The plasma IL-1 and IL-6 levels were measured using commercial Bio Plex Multi Assay Technology kits (Bio Rad Laboratories, USA). Plasma renin activity was measured using the Active Renin IRMA DLS-25100 commercial kit (Diagnostic Systems Laboratories, Inc. USA), and aldosterone was measured with a solid-phase radioimmunoassay using the Coat A Count Aldosterone kit (Diagnostic Product Corporation, Los Angeles, CA, USA). The LPO products, expressed as malondialdehyde acid (MDA), were measured using high-pressure liquid chromatography coupled with a commercial LPO-586 kit (Oxis International, Inc., Portland, OR, USA) [14]. SOD was measured using a SOD Assay Kit-WST (Sigma), which involves a method based on tetrazolium oxidation. GPx activity was evaluated using spectrophotometry based on reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidation with the commercial Glutathione Assay Kit (K264-100, Vision Inc., Mountain View, CA, USA) [15]. Total glutathione, defined as the sum of reduced glutathione and oxidized glutathione, was assayed using enzyme testing coupled with glutathione reductase [16].

Statistical Analysis

The quantitative variables were assessed by examining the mean ± standard deviation, and the qualitative variables were evaluated as frequencies and percentages. The comparison of the means between groups was performed using the Student's t-test for independent data, and their comparison over time was carried out using anova for repeated measurements.

Results

The study groups were homogenous, with no significant differences according to the age, stone size, number of applied shockwave impacts and studied variables (Table 1). No patient had any complications, e.g. fever, significant colicky pain, ureteric obstruction due to so-called steinstrasse and aggravated hydronephrosis after ESWL.

Table 1. The baseline characteristics of the study groups
VariableCoQ10 groupPlacebo groupP
N5050 
Mean (sd):   
Age, years49.85 (11.45)50.60 (10.77)0.74
Size of stone, mm12.57 (6.76)12.65 (6.09)0.95
Number of impacts2622.22 (308.87)2678.85 (358.83)0.41
Renal injury parameters:   
GFR (MDRD), mL/min98.42 (17.3)93.3 (17.58)0.55
Albumin/creatinine ratio, mg/g70 (80)90 (130)0.59
β2-microglobulin, μg/L1904.67 (1120)1696.52 (418)0.23
Vasoactive hormone markers:   
Renin, pg/mL11.45 (7.9)11.36 (8.35)0.57
Aldosterone, pg/mL171.9 (101)192.42 (130.7)0.51
VRI0.62 (0.08)0.63 (0.11)0.23
Interleukins:   
IL-1, pg/mL0.26 (0.12)0.27 (0.41)0.86
IL-6, pg/mL4.28 (4.6)5.12 (5.57)0.42
Oxidative stress markers:   
LPO, μM0.22 (0.1)0.23 (0.1)0.77
SOD, U/L4.76 (3)5.28 (4.34)0.44
GPx, U/L34.94 (14)36.42 (14.7)0.68
GSH, nmol/mL4.43 (1.8)4.82 (2.48)0.49

Effect of CoQ10 on Renal Injury Parameters

At 1 week after initiation of drug administration, there was a significant increase in GFR values and a decrease in the albumin/creatinine ratio and β2-microglobulin in the CoQ10 group compared with the baseline values (Table 2). While, no differences were seen in the placebo group at 1 week of treatment compared with the baseline values (Table 2).

Table 2. Renal function evaluation before and after ESWL in the placebo group (PG) and the CoQ10 group
VariableGroupBaseline2 h before ESWL2 h after ESWL24 h after ESWL7 days after ESWL
  1. (1)P = 0.013; (2)P = 0.02 compared to baseline; (3)P = 0.01; (4)P = 0.004; (5)P = 0.02; (6)P = 0.01; (7)P = 0.001 compared with pre-lithotripsy levels; (8)P = 0.005; (9)P = 0.01; (10)P = 0.001; (11)P < 0.001; (12)P = 0.04; (13)P = 0.008 compared with the PG. Albumin/creatinine ratio was calculated in urine and β2-microglobulin in serum.
Mean (sd):      
GFR (MDRD), mL/minCoQ1098.42 (17.3)102.56 (17.7)(1) (8)104.9 (16.8)93.3 (18)(3)93 (20)(9)
PG93.3 (17.58)92.14 (17.42)97.7 (20)88.6 (16)(3)82.79 (20)
Albumin/creatinine ratio, mg/gCoQ1070 (80)50 (50)(2) (9)70 (60)(4) (11)150 (150)(9)50 (80)(12)
PG90 (130)120 (140)210 (240)(5)290 (220)(6)80 (100)(7)
β2-microglobulin, μg/LCoQ101904.67 (1120)1480.9 (265)(2) (10)1504 (569)(9)1643 (666)1657 (419)(13)
PG1696.52 (418)1720.76 (353.6)1721 (361)1669 (592)1918 (508)

When the CoQ10 group was compared with the placebo group, a significant improvement was seen in the GFR value (P = 0.005), the albumin/creatinine ratio (P = 0.01) and the β2-microglobulin value (P = 0.001) at 1 week after treatment (Table 2).

At the ESWL follow-up, the CoQ10 group maintained a significant improvement in GFR value, albumin/creatinine ratio and β2-microglobulin value, especially in the albumin/creatinine ratio, which presented levels within the lower limit of microalbuminuria (Fig. 2a–c).

Figure 2.

(a) GFR evaluation (MDRD) before and after ESWL in the CoQ10 group and the placebo group (PG). (b) Albumin/creatinine ratio evaluation before and after ESWL in the CoQ10 group and the PG. (c) β2-microglobulin evaluation before and after ESWL in the CoQ10 group and the PG.

Effect of CoQ10 on Vasoactive Hormone Markers and Renal Vascular Resistance

The administration of CoQ10 for 1 week, induced a rapid reduction of hormone levels, related to the renin-angiotensin axis. The levels of renin (P = 0.01) and aldosterone (P = 0.04) significantly decreased vs the levels in the placebo group (Table 3).

Table 3. Serum vasoactive hormone evaluation before and after ESWL in the CoQ10 group and the placebo group (PG)
VariableGroupBaseline2 h before ESWL2 h after ESWL24 h after ESWL7 days after ESWL
  1. (1)P = 0.04; (2)P = 0.09 compared with baseline; (3)P = 0.001; (4)P < 0.001; (5)P = 0.04 compared with pre-lithotripsy levels; (6)P = 0.01; (7)P = 0.04; (8)P = 0.03; (9)P = 0.02 compared with the PG.
Mean (sd):      
Renin, pg/mLCoQ1011.45 (7.9)9.39 (5.5)(1) (6)13.8 (0)(3) (8)10.1 (5.6)(8)11.38 (9.2)(8)
PG11.36 (8.35)15.37 (23.97)22 (33)(3)17 (15)17.7 (21)
Aldosterone, pg/mLCoQ10171.9 (101)154.88 (90)(2) (7)272 (129)(4)132 (65)(5) (9)178 (74)
PG192.42 (130.7)189.96 (111.16)285 (183)(3)160 (13)186 (121)
VRICoQ10   0.63 (0.09)(5)0.61 (0.08)(8)
PG   0.64 (0.08)(5)0.65 (0.1)(5)

The progression of renin, aldosterone and VRI values after ESWL in the CoQ10 group paralleled those of the placebo group, although the overall levels were lower, achieving at 1 week of treatment values similar to those seen at baseline (Table 3, Fig. 3).

Figure 3.

(a) Renin levels before and after ESWL in the CoQ10 group and the placebo group (PG). (b) Aldosterone levels before and after ESWL in the CoQ10 group and the PG. (c) VRI before and after ESWL in the CoQ10 group and the PG.

Effect of CoQ10 on Interleukins

There was a significant reduction in IL-6 (P = 0.02) after 1 week in the CoQ10 treatment group vs the placebo group (Table 4). The decrease in cytokines seen after administration of CoQ10 before ESWL was maintained over the course of the ESWL follow-up period (Table 4, Fig. 4).

Figure 4.

(a) IL-1 levels before and after ESWL in the CoQ10 group and the placebo group (PG). (b) IL-6 levels before and after ESWL in the CoQ10 group and the PG.

Table 4. Serum interleukin evaluation before and after ESWL in the CoQ10 group and the placebo group (PG)
VariableGroupBaseline2 h before ESWL2 h after ESWL24 h after ESWL7 days after ESWL
  1. (1)P = 0.02; (2)P = 0.001 compared with pre-lithotripsy levels; (3)P = 0.02; (4)P = 0.03; (5)P = 0.01; (6)P = 0.006; (7)P = 0.009 compared with the PG.
Mean (sd):      
IL-1, pg/mLCoQ100.26 (0.12)0.25 (0.120.27 (0.1)(4)0.3 (0.1)0.20 (0.2)
PG0.27 (0.41)0.27 (0.310.42 (0.3)(1)0.37 (0.2)(1)0.25 (0.2)
IL-6, pg/mLCoQ104.28 (4.6)3.75 (2.3)(3)3.7 (2.2)(5)7 (5)(2) (6)4.7 (4)(7)
PG5.12 (5.57)5.54 (4.47)5.53 (4.7)11.57 (6)(2)7.69 (5.6)(1)

Effect of CoQ10 on Oxidative Stress Markers

CoQ10 administration was not associated with significant changes in most of the studied parameters related to oxidative stress (Table 5).

Table 5. Evaluation of serum oxidative stress markers before and after ESWL in the CoQ10 group and the placebo group (PG)
VariableGroupBaseline2 h before ESWL2 h after ESWL24 h after ESWL7 days after ESWL
  1. (1)P = 0.007; (2)P = 0.05 compared with pre-lithotripsy levels. (3)P = 0.03 compared with the PG.
LPO, μmCoQ100.22 (0.1)0.23 (0.1)0.27 (0.1)0.21 (0.06)(1)(3)0.23 (0.1)
PG0.23 (0.1)0.25 (0.1)0.25 (0.09)0.24 (0.08)0.23 (0.06)
SOD, U/LCoQ104.76 (3)4.14 (1.7)5.6 (4.8)(2)4.86 (2.9)4.6 (2.5)
PG5.28 (4.34)4.72 (2.6)4.88 (3)4.37 (2.7)4.3 (1.94)
GPx, U/LCoQ1034.94 (14)36.5 (15)34.6 (7.7)35.09 (11)33 (15.8)
PG36.42 (14.7)34.83 (11.6)34.6 (10.7)37.1 (14)34 (13)
GSH, nmol/mLCoQ104.43 (1.8)5.39 (1.2)4.97 (2)4.79 (2.04)5.07 (1.75)
PG4.82 (2.48)5.4 (3.4)4.77 (2.4)4.41 (2.14)4.77 (2.57)

CoQ10 promoted a significant increase in SOD activity (P = 0.05) at 2 h after ESWL vs placebo. The significant decrease in the LPO levels seen at the 24-h follow-up in the CoQ10 resulted from the fact that at 2-h follow up, the levels had clearly increased to 0.27 μM, making them higher than the levels seen in the placebo group (Table 5). Overall, the GSH levels in the CoQ10 group were higher than in the placebo group. However, these differences were not significant (Table 5).

Discussion

ESWL is currently a treatment option for most cases of urolithiasis, Nevertheless, the procedure is not completely free of side-effects because it can induce an acute alteration in renal function as reported in previous studies [4, 17, 18]. However, the mechanisms facilitating their development are not well defined. The effects of vasoactive hormone pro-inflammatory mediators and oxidative stress have all been hypothesised as potential mechanisms underlying this type of renal damage [6, 19-21].

Although a small cohort of patients was enrolled, the present randomised study is the first clinical report showing that the administration of CoQ10 peri-ESWL may be a therapeutic option in the prevention of glomerular and tubular damage caused by ESWL. In addition, the cost of this treatment is low (45€/patient), but further studies are necessary to elucidate if it would be worth administering CoQ10 to every patient undergoing ESWL and if this treatment is cost-effective.

ESWL Associated Injury

As mentioned above, several studies have described acute deterioration of renal function after shockwave treatment [20, 21]. It has been postulated that constriction of the renal parenchyma after the shockwave alters intrarenal haemodynamics [22]. In the present study, when analysing the GFR after ESWL, there was an increase at the 2-h follow-up, while at 24 h and 1 week after ESWL, there was a significant decrease to values lower than those at baseline. The present findings are concordant with these previous studies.

The plasma level of β2-microglobulin, which is synthesised by different cell types, such as lymphocytes, was used as a marker of renal damage. Several studies have shown an increase in β2-microglobulin after treatment with ESWL [23]. Nevertheless, the primary early marker of renal damage is elevated urine albumin secretion even without an accompanying decrease in GFR [24]. Sen et al. [25] found a transient increase in albuminuria immediately after ESWL that returned to normal without resulting in any sequelae. In the present study, there was a significant increase in the albumin/creatinine ratio at 2 h after ESWL, which returned to normal values at the 1-week follow-up. These results are in contrast to the β2-microglobulin levels, which remained elevated even at the 1-week follow-up. A longer period was necessary for these levels to return to normal. These findings are concordant with previous studies [20, 23, 25].

After the initial increase in GFR due to prostaglandin-mediated vasodilation, there was a decrease in GFR due to a vasoconstriction phenomenon with an increase in intrarenal resistance resulting from a self-defence mechanism caused by vasoactive mediators, such as renin, angiotensin II and endothelins [22]. In the present study, the levels of renin, and more markedly aldosterone, increased after the ESWL session. When we evaluated VRI using Doppler ultrasound, a significant increase in VRI was seen after ESWL. These findings are in agreement with Janetschek et al. [26], who found increased VRI in the treated kidneys of patients who underwent ESWL. In addition, this overexpression of renin with a subsequent increase in angiotensin promotes the release of oxygen-free radicals (OFR) via activation of the NADPH oxidase, with the resulting activation of pro-inflammatory molecules that contribute to kidney damage [27]. IL-1 production induces the release of IL-6 [28], which explains the earlier increase of IL-1 compared with IL-6 concentration in the blood after ESWL. As in the present study, other experimental studies in pigs have also shown increased IL-6 levels after ESWL [29].

Another fundamental aspect of the present study was the evaluation of oxidative stress markers after ESWL. As mentioned above, these levels can be affected by the pro-oxidant effect of the activation of the renin-angiotensin system. An ischaemia-reperfusion phenomenon occurs during shockwave treatment. Various experimental models have shown that renal tissue suffers morphological and functional damage during periods of ischaemia that is increased during reperfusion [30]. OFRs have been implicated in promoting this damage via the lipoperoxidation of cellular membranes and organelles, which causes damage to cellular integrity and alters cellular transport and energy production capacity [31]. Bomanji et al. [32] reported a decrease in renal perfusion after ESWL that was associated with the production of different OFRs. Aksoy et al. [5] reported an increase in MDA and nitric oxide in plasma and urine immediately after a shockwave session. However, as in the present study, neither a study by Clark et al. [33] nor a previous study [34] found changes in LPO levels. For oxidative stress in the present study, there were only slight decreases in GSH and SOD at the 2- and 24-h follow-ups.

These findings may be due to the fragility and transient nature of OFRs, which might have led to measurement at an intermediate stage of return to baseline or, as noted by Delvecchio et al. [35] in an experimental study of pigs, the oxidative stress may be more pronounced in the area of shockwave impact than in the plasma, suggesting that the inflammation and oxidative stress seen after ESWL are localised rather than systemic responses. Future studies should analyse oxidative stress after ESWL in the renal cortex and medulla, which appear to be more susceptible to the resulting hypoxia after the shockwave session [29].

Effect of Administering CoQ10 for 2 weeks in Sessions Associated with ESWL

The administration of CoQ10 reduced different marker values of renal dysfunction in patients who received ESWL. CoQ10 improved GFR, the albumin/creatinine ratio and β2-microglobulin, which suggest that the ubiquinone supplementation provided protection at both the glomerular and tubular renal levels. In addition, treatment with CoQ10 has been reported to have a beneficial effect on vasoactive hormone markers after ESWL. A reduction in peripheral resistances was also achieved, which may be due to direct action on the vascular endothelium [36]. Plasma decreases in renin and aldosterone concentration have a beneficial effect on renal vasoconstriction that is associated with the activation of the renin-angiotensin system during renal injury, as well as from the activation of the proinflammatory cytokine cascade [37].

In the present study, the administration of CoQ10 reduced IL-1 and IL-6 levels at 1 week after ESWL compared with the placebo group. The IL-6 level differences were significantly different. These changes may have also been associated with the decreased renin-angiotensin activity seen in the treated patients.

The effect of CoQ10 on oxidative stress was unexpected. It has been shown that CoQ10 exerts a beneficial effect in ATP synthesis, in addition to preventing oxidative stress and the peroxidation of lipids and proteins. These effects give it an important role in modulating the damage caused by oxidative stress during ischaemia and reperfusion [38]. The present study did not demonstrate a serum increase of LPO and reduction of antioxidant status as a consequence of ESWL in patients with renal lithiasis. The measurement of LPOs and antioxidants in renal tissue would be more reliable than measurements in the renal cortex and medulla, which appear to be highly susceptible to the OFRs [29]. In addition, a higher drug dose or a longer treatment time may be necessary to detect its effect in serum.

In conclusion, in the present study, CoQ10 administrated peri-ESWL determined an improvement of renal injury and a decrease in renin-aldosterone axis and pro-inflammatory mediator levels. Thus, the results of the present study support the use of CoQ10 as protective drug in patients with renal lithiasis undergoing ESWL.

Conflict of Interest

Drs. Javier Padillo, Julia Carrasco and Maria J. Requena hold a patent with the Spanish Office of Patents and Trademarks.

All other authors declare no conflict of interest.

Abbreviations
CoQ10

coenzyme Q10

ESWL

extracorporeal shockwave lithotripsy

GPx

glutathione peroxidase

GSH

reduced glutathione

IL(-1)(-6)

interleukin (1) (6)

LPO

lipoperoxides

MDA

malondialdehyde acid

MDRD

Modification of Diet in Renal Disease

NADPH

nicotinamide adenine dinucleotide phosphate

OFR

oxygen-free radicals

SOD

superoxide dismutase

VRI

vascular resistance index

Ancillary