Clin Exp Nephrol DOI 10.1007/s10157-013-0884-7
ORIGINAL ARTICLE
Immediate and long-term high levels of plasma homocysteine after extracorporeal shock wave lithotripsy in patients with renal stone disease Erkan Demir • Volkan Izol • I. Atilla Aridogan Saime Paydas • Zuhtu Tansug • Ugur Erken
•
Received: 28 June 2013 / Accepted: 27 September 2013 Ó Japanese Society of Nephrology 2014
Abstract Background Plasma homocysteine levels increase in patients with chronic renal failure. Numerous studies have demonstrated that kidney function is one of the most important determinants of plasma total homocysteine (tHcy) concentration. In this study we aimed to evaluate the relationship between tHcy levels and extracorporeal shock wave lithotripsy (ESWL) for patients with renal stones and to see if the change in homocysteine levels continued if renal dysfunction improved. Materials and methods The study consisted of 20 patients who underwent first-time ESWL for renal stones. Every patient gave 3 blood samples at 24 h before surgery and at 2 days and at 3 months after ESWL for measurement of plasma levels of tHcy, creatinine, vitamin B6, and vitamin B12. Results The 20 patients (12 male, 8 female) had a mean age of 42.8 ± 11.7 years. tHcy levels showed a statistically significant increase from 9.4 ± 1.4 to 18 ± 4.8 and 11.2 ± 2.1 at 2 days and at 3 months, respectively. Serum creatinine also showed a statistically significant increase compared to baseline at 2 days and at 3 months after ESWL. Conclusion After first-time ESWL, the increase in serum levels of creatinine and tHcy due to renal injury, such as ischemia/reperfusion injury, may be severe and continue for a long period, such as 3 months. According to baseline E. Demir V. Izol (&) I. A. Aridogan Z. Tansug U. Erken Department of Urology, Faculty of Medicine, University of C¸ukurova, 01330 Adana, Turkey e-mail: [email protected] S. Paydas Department of Nephrology, Faculty of Medicine, University of C¸ukurova, Adana, Turkey
levels, the increase in homocysteine levels as an indicator of oxidant stress was more severe than the creatinine levels after ESWL for renal stones. Our patients were first-time ESWL patients; however, in patients who undergo EWSL more than once long-term high tHcy levels should also be considered as renal. Keywords Homocysteine Shock wave lithotripsy Glomerular filtration rate Renal injury
Introduction Homocysteine is a sulfur-containing amino acid formed through the de-methylation of methionine. Elevated total homocysteine (tHcy) levels have been associated with atherothrombotic vascular disease in the general population [1]. Since tHcy levels are markedly elevated in patients with chronic renal failure, it has been presented as a potential factor contributing to the high risk of cardiovascular disease in these patients [2]. Extracorporeal shock wave lithotripsy (ESWL) is the preferred method for treating kidney stones \2 cm in size. The impact of ESWL on renal function has been evaluated in many studies. Many indicators have been used for this purpose such as serum creatinine, DTPA scan, ultrasonography and MAG3 scan. In these studies a dramatic decrease in glomerular filtration rate (GFR) was reported during the first few hours after ESWL for renal stones [3, 4]. It was also found that plasma tHcy levels were negatively correlated with GFR [5]. In fact, impaired renal function may be the most important determinant of tHcy concentration in plasma. In this study, we evaluated the relationship between tHcy levels and ESWL for patients with renal stones. We also followed up whether the change
123
Clin Exp Nephrol
in the levels of creatinine and homocysteine as an indicator of oxidant stress, continued in the long-term.
Table 1 Comparison of biochemical parameters in patients before and after ESWL Parameters
Before ESWL
2 days
Patients and methods tHcy (lmol/L)
Twenty patients with nephrolithiasis were evaluated 24 h before ESWL and at 2 days and at 3 months after ESWL. Fasting blood samples were drawn and separated within 30 min for measurements of fasting tHcy, creatinine, folate, vitamin B12, and vitamin B6. This study was approved by the local Ethics Committee with an approval number 5, and all subjects gave their informed consent. The patients were evaluated for baseline assessment of renal function including serum creatinine, blood urea nitrogen, potassium, sodium, uric acid, and liver function tests. Urine culture and intravenous urography were also performed before ESWL. Stone diameter was measured on an abdominal plain film. ESWL therapy is usually started at a low voltage until the patient becomes accustomed to the shocks, and the voltage is then gradually increased to a maximum of 65 % for the kidney. The shock waves were delivered at rate of 80–90 shock waves/min as advised by some authors; the mean number of shocks per session was 3,000 for kidney (Elmed Lithotripsy Systems, Ankara, Turkey). Patients received 100 lg fentanyl prior to ESWL with intermittent fluoroscopy. Patients with renal impairment who developed postESWL complications such as steinstrasse, sepsis or ureteric obstruction that required further intervention were excluded from the study. The fasting tHcy concentration was measured in plasma from EDTA-anticoagulated blood with the use of highpressure liquid chromatography and fluorometric detection. Statistical analysis We analyzed non-normal distributed data with the use of the Mann–Whitney U test. The Bonferroni method was used to correct for multiple comparisons. Correlations between parameters were calculated with the use of Spearman’s rank-correlation test. p values of \0.05 were considered statistically significant. All values are expressed as mean ± standard deviation.
Results Of the patients, 12 (60 %) were male and 8 (40 %) were female with a mean age of 42.8 ± 11.7 years (24–61). The changes in the tHcy values before and after ESWL for the 20 patients are shown in Table 1. We noted significant
123
After ESWL
9.4 ± 1.4
3 months
18 ± 4.8* *
11.2 ± 2.1* 0.94 ± 0.2*
Creatinine (mg/dL)
0.86 ± 0.19
1.2 ± 0.4
tHcy % increase over baseline
–
62 ± 32
21 ± 28
Creatinine % increase over baseline
–
38 ± 14
13 ± 5.8
Folate (ng/mL)
Vitamin B12 (pg/mL)
Vitamin B6 (nmol/L)
10.2 ± 3.7
10.9 ± 3.6
11.4 ± 3.9
12.4 (4.2–16.2)a
11.8 (4.8–16.8)a
11.8 (3.9–16.8)a
241 ± 171
246 ± 164
255 ± 158
266 (218–544)a
259 (229–498)a
288 (241–504)a
73 ± 102
68 ± 98
76 ± 110
63 (31–197)a
65 (32–220)a
70 (30–228)a
a
Median value
*
p \ 0.05 vs pre-ESWL value
increases in mean tHcy and creatinine concentrations among the patients at 2 days and at 3 months after ESWL compared with the mean pre-ESWL levels (p \ 0.05). Comparison of the percent increases in tHcy and creatinine concentrations after surgery with the pre-surgery baseline values shows that tHcy and creatinine levels increased by 62 and 38 %, respectively, and then gradually diminished, although neither returned to its pre-surgery value. No significant changes in the concentration of folate, vitamin B12, or vitamin B6 were observed during the 3-month study period, and we noted a significant positive correlation between fasting tHcy and creatinine value (r = 0.679, p \ 0.001).
Discussion ESWL has become a routine method for the treatment of upper urinary tract stone disease. Despite its proven safety and efficacy, there have been several studies on the complications occurring after ESWL. Many studies reported a decrease in GFR during the first few hours after ESWL [3, 4]. As in previously published data, it was stated that increased urinary enzymes such as lactate dehydroxygenase and glutamate oxalacetate transaminase were reported after ESWL treatment [6]. Elevations in plasma tHcy levels may be caused by folate and vitamin B12 deficiencies, which are cofactors for the enzyme reactions involved in Hcy metabolism [7].
Clin Exp Nephrol
Renal insufficiency is invariably accompanied by elevated plasma concentrations of potentially vasculotoxic amino acid homocysteine. There is a strong relationship between GFR and plasma homocysteine concentration [5, 8]. This study included 20 patients treated with ESWL for nephrolithiasis. We measured the concentrations of homocysteine, creatinine, folate, vitamin B12, and vitamin B6 before surgery and at 2 days and at 3 months after ESWL. ESWL caused increases in the plasma levels of creatinine and tHcy. The mean plasma tHcy concentration increased by 62 % at 2 days after ESWL. Thereafter, the level decreased until 3 months after ESWL; the mean concentration was just 21 % greater than the pre-ESWL level. Both the increase in tHcy level and the subsequent decrease were relatively paralleled by the changes in plasma creatinine values, as shown by the unadjusted Spearman correlation coefficient of 0.679. In contrast to the creatinine concentration, which was significantly correlated with the changes in plasma tHcy levels, none of the other measured parameters correlated with tHcy levels to the same degree. Although hyperhomocysteinemia is well known as an indicator of oxidant stress and homocysteine-dependent endothelial dysfunction [1, 2], we did not find any data between increased cardiovascular risk and high levels of tHcy following ESWL. Tsai et al. [9] demonstrated a correlation between GFR and plasma tHcy in healthy individuals who underwent uninephrectomy for kidney donation. In their study, they showed an increase in the creatinine and tHcy levels on the 2nd postoperative day. There was then a gradual decrease until the 6th postoperative month; however, the levels at the 6th postoperative month were still higher than the pre-surgery levels. They concluded that their model strongly supported the hypothesis that renal metabolism of tHcy is the mechanism responsible for the correlation between renal function and plasma tHcy levels. In our study similar results were obtained on the post-ESWL 2nd day and 3rd month. tHcy levels were initially increased and then gradually decreased; however, the levels were still significantly higher than the pre-ESWL levels as also found in volunteers who underwent uninephrectomy for kidney donation. The two limitations of our study were the low number of patients and the short follow-up time. Furthermore, we were unable to determine the tHcy levels more frequently due to limited financial sources and tHcy kits. It would be useful to explain where the maximum alteration of the renal tubulus had disappeared and to predict the interval
between repeated ESWL sessions. In the literature, there are no conclusive data on the intervals required between repeated ESWL sessions. However, we believe that further studies with larger series and other definitive parameters are needed to define the effects of ESWL. It is known that ESWL reduces GFR levels. In conclusion, to the best of our knowledge, this study is the first to document plasma Hcy levels before and after ESWL in patients with nephrolithiasis. Plasma tHcy as well as creatinine levels increase and remain high after ESWL, and this shows that in the long-term the kidney function does not return to baseline. The patients included in our study were first-time ESWL patients. High tHcy levels should be taken into consideration especially in patients who underwent ESWL more than once. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Vanizor Kural B, Orem A, Cims¸ it G, Uydu HA, Yandi YE, Alver A. Plasma homocysteine and its relationships with atherothrombotic markers in psoriatic patients. Clin Chim Acta. 2003;332:23–30. 2. Tsai MY. Moderate hyperhomocysteinemia and cardiovascular disease. J Lab Clin Med. 2000;135:16–25. 3. Willis LR, Evan AP, Connors BA, Reed G, Fineberg NS, Lingeman JA. Effects of extracorporeal shock wave lithotripsy to one kidney on bilateral glomerular filtration rate and PAH clearance in minipigs. J Urol. 1996;156:1502–6. 4. Vlajkovic´ M, Slavkovic´ A, Radovanovic´ M, Siric´ Z, Stefanovic´ V, Perovic´ S. Long-term functional outcome of kidneys in children with urolithiasis after ESWL treatment. Eur J Pediatr Surg. 2002;12:118–23. 5. Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Lab Invest. 1996;56:41–6. 6. Strohmaier WL, Bichler KH, Deetjen P, Kleinknecht S, Pedro M, Wilbert DM. Damaging effects of high energy shock waves on cultured Madin Darby canine kidney (MDCK) cells. Urol Res. 1990;18:255–8. 7. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049–57. 8. Wollesen F, Brattstro¨m L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int. 1999;55:1028–35. 9. Tsai MY, Aras O, Sozen H, Hanson NQ, Woll PS, Arends VL, Hunninghake DB, Matas AJ. Plasma homocysteine levels in living kidney donors before and after uninephrectomy. J Lab Clin Med. 2004;143:340–3.
123
ORIGINAL ARTICLE
Immediate and long-term high levels of plasma homocysteine after extracorporeal shock wave lithotripsy in patients with renal stone disease Erkan Demir • Volkan Izol • I. Atilla Aridogan Saime Paydas • Zuhtu Tansug • Ugur Erken
•
Received: 28 June 2013 / Accepted: 27 September 2013 Ó Japanese Society of Nephrology 2014
Abstract Background Plasma homocysteine levels increase in patients with chronic renal failure. Numerous studies have demonstrated that kidney function is one of the most important determinants of plasma total homocysteine (tHcy) concentration. In this study we aimed to evaluate the relationship between tHcy levels and extracorporeal shock wave lithotripsy (ESWL) for patients with renal stones and to see if the change in homocysteine levels continued if renal dysfunction improved. Materials and methods The study consisted of 20 patients who underwent first-time ESWL for renal stones. Every patient gave 3 blood samples at 24 h before surgery and at 2 days and at 3 months after ESWL for measurement of plasma levels of tHcy, creatinine, vitamin B6, and vitamin B12. Results The 20 patients (12 male, 8 female) had a mean age of 42.8 ± 11.7 years. tHcy levels showed a statistically significant increase from 9.4 ± 1.4 to 18 ± 4.8 and 11.2 ± 2.1 at 2 days and at 3 months, respectively. Serum creatinine also showed a statistically significant increase compared to baseline at 2 days and at 3 months after ESWL. Conclusion After first-time ESWL, the increase in serum levels of creatinine and tHcy due to renal injury, such as ischemia/reperfusion injury, may be severe and continue for a long period, such as 3 months. According to baseline E. Demir V. Izol (&) I. A. Aridogan Z. Tansug U. Erken Department of Urology, Faculty of Medicine, University of C¸ukurova, 01330 Adana, Turkey e-mail: [email protected] S. Paydas Department of Nephrology, Faculty of Medicine, University of C¸ukurova, Adana, Turkey
levels, the increase in homocysteine levels as an indicator of oxidant stress was more severe than the creatinine levels after ESWL for renal stones. Our patients were first-time ESWL patients; however, in patients who undergo EWSL more than once long-term high tHcy levels should also be considered as renal. Keywords Homocysteine Shock wave lithotripsy Glomerular filtration rate Renal injury
Introduction Homocysteine is a sulfur-containing amino acid formed through the de-methylation of methionine. Elevated total homocysteine (tHcy) levels have been associated with atherothrombotic vascular disease in the general population [1]. Since tHcy levels are markedly elevated in patients with chronic renal failure, it has been presented as a potential factor contributing to the high risk of cardiovascular disease in these patients [2]. Extracorporeal shock wave lithotripsy (ESWL) is the preferred method for treating kidney stones \2 cm in size. The impact of ESWL on renal function has been evaluated in many studies. Many indicators have been used for this purpose such as serum creatinine, DTPA scan, ultrasonography and MAG3 scan. In these studies a dramatic decrease in glomerular filtration rate (GFR) was reported during the first few hours after ESWL for renal stones [3, 4]. It was also found that plasma tHcy levels were negatively correlated with GFR [5]. In fact, impaired renal function may be the most important determinant of tHcy concentration in plasma. In this study, we evaluated the relationship between tHcy levels and ESWL for patients with renal stones. We also followed up whether the change
123
Clin Exp Nephrol
in the levels of creatinine and homocysteine as an indicator of oxidant stress, continued in the long-term.
Table 1 Comparison of biochemical parameters in patients before and after ESWL Parameters
Before ESWL
2 days
Patients and methods tHcy (lmol/L)
Twenty patients with nephrolithiasis were evaluated 24 h before ESWL and at 2 days and at 3 months after ESWL. Fasting blood samples were drawn and separated within 30 min for measurements of fasting tHcy, creatinine, folate, vitamin B12, and vitamin B6. This study was approved by the local Ethics Committee with an approval number 5, and all subjects gave their informed consent. The patients were evaluated for baseline assessment of renal function including serum creatinine, blood urea nitrogen, potassium, sodium, uric acid, and liver function tests. Urine culture and intravenous urography were also performed before ESWL. Stone diameter was measured on an abdominal plain film. ESWL therapy is usually started at a low voltage until the patient becomes accustomed to the shocks, and the voltage is then gradually increased to a maximum of 65 % for the kidney. The shock waves were delivered at rate of 80–90 shock waves/min as advised by some authors; the mean number of shocks per session was 3,000 for kidney (Elmed Lithotripsy Systems, Ankara, Turkey). Patients received 100 lg fentanyl prior to ESWL with intermittent fluoroscopy. Patients with renal impairment who developed postESWL complications such as steinstrasse, sepsis or ureteric obstruction that required further intervention were excluded from the study. The fasting tHcy concentration was measured in plasma from EDTA-anticoagulated blood with the use of highpressure liquid chromatography and fluorometric detection. Statistical analysis We analyzed non-normal distributed data with the use of the Mann–Whitney U test. The Bonferroni method was used to correct for multiple comparisons. Correlations between parameters were calculated with the use of Spearman’s rank-correlation test. p values of \0.05 were considered statistically significant. All values are expressed as mean ± standard deviation.
Results Of the patients, 12 (60 %) were male and 8 (40 %) were female with a mean age of 42.8 ± 11.7 years (24–61). The changes in the tHcy values before and after ESWL for the 20 patients are shown in Table 1. We noted significant
123
After ESWL
9.4 ± 1.4
3 months
18 ± 4.8* *
11.2 ± 2.1* 0.94 ± 0.2*
Creatinine (mg/dL)
0.86 ± 0.19
1.2 ± 0.4
tHcy % increase over baseline
–
62 ± 32
21 ± 28
Creatinine % increase over baseline
–
38 ± 14
13 ± 5.8
Folate (ng/mL)
Vitamin B12 (pg/mL)
Vitamin B6 (nmol/L)
10.2 ± 3.7
10.9 ± 3.6
11.4 ± 3.9
12.4 (4.2–16.2)a
11.8 (4.8–16.8)a
11.8 (3.9–16.8)a
241 ± 171
246 ± 164
255 ± 158
266 (218–544)a
259 (229–498)a
288 (241–504)a
73 ± 102
68 ± 98
76 ± 110
63 (31–197)a
65 (32–220)a
70 (30–228)a
a
Median value
*
p \ 0.05 vs pre-ESWL value
increases in mean tHcy and creatinine concentrations among the patients at 2 days and at 3 months after ESWL compared with the mean pre-ESWL levels (p \ 0.05). Comparison of the percent increases in tHcy and creatinine concentrations after surgery with the pre-surgery baseline values shows that tHcy and creatinine levels increased by 62 and 38 %, respectively, and then gradually diminished, although neither returned to its pre-surgery value. No significant changes in the concentration of folate, vitamin B12, or vitamin B6 were observed during the 3-month study period, and we noted a significant positive correlation between fasting tHcy and creatinine value (r = 0.679, p \ 0.001).
Discussion ESWL has become a routine method for the treatment of upper urinary tract stone disease. Despite its proven safety and efficacy, there have been several studies on the complications occurring after ESWL. Many studies reported a decrease in GFR during the first few hours after ESWL [3, 4]. As in previously published data, it was stated that increased urinary enzymes such as lactate dehydroxygenase and glutamate oxalacetate transaminase were reported after ESWL treatment [6]. Elevations in plasma tHcy levels may be caused by folate and vitamin B12 deficiencies, which are cofactors for the enzyme reactions involved in Hcy metabolism [7].
Clin Exp Nephrol
Renal insufficiency is invariably accompanied by elevated plasma concentrations of potentially vasculotoxic amino acid homocysteine. There is a strong relationship between GFR and plasma homocysteine concentration [5, 8]. This study included 20 patients treated with ESWL for nephrolithiasis. We measured the concentrations of homocysteine, creatinine, folate, vitamin B12, and vitamin B6 before surgery and at 2 days and at 3 months after ESWL. ESWL caused increases in the plasma levels of creatinine and tHcy. The mean plasma tHcy concentration increased by 62 % at 2 days after ESWL. Thereafter, the level decreased until 3 months after ESWL; the mean concentration was just 21 % greater than the pre-ESWL level. Both the increase in tHcy level and the subsequent decrease were relatively paralleled by the changes in plasma creatinine values, as shown by the unadjusted Spearman correlation coefficient of 0.679. In contrast to the creatinine concentration, which was significantly correlated with the changes in plasma tHcy levels, none of the other measured parameters correlated with tHcy levels to the same degree. Although hyperhomocysteinemia is well known as an indicator of oxidant stress and homocysteine-dependent endothelial dysfunction [1, 2], we did not find any data between increased cardiovascular risk and high levels of tHcy following ESWL. Tsai et al. [9] demonstrated a correlation between GFR and plasma tHcy in healthy individuals who underwent uninephrectomy for kidney donation. In their study, they showed an increase in the creatinine and tHcy levels on the 2nd postoperative day. There was then a gradual decrease until the 6th postoperative month; however, the levels at the 6th postoperative month were still higher than the pre-surgery levels. They concluded that their model strongly supported the hypothesis that renal metabolism of tHcy is the mechanism responsible for the correlation between renal function and plasma tHcy levels. In our study similar results were obtained on the post-ESWL 2nd day and 3rd month. tHcy levels were initially increased and then gradually decreased; however, the levels were still significantly higher than the pre-ESWL levels as also found in volunteers who underwent uninephrectomy for kidney donation. The two limitations of our study were the low number of patients and the short follow-up time. Furthermore, we were unable to determine the tHcy levels more frequently due to limited financial sources and tHcy kits. It would be useful to explain where the maximum alteration of the renal tubulus had disappeared and to predict the interval
between repeated ESWL sessions. In the literature, there are no conclusive data on the intervals required between repeated ESWL sessions. However, we believe that further studies with larger series and other definitive parameters are needed to define the effects of ESWL. It is known that ESWL reduces GFR levels. In conclusion, to the best of our knowledge, this study is the first to document plasma Hcy levels before and after ESWL in patients with nephrolithiasis. Plasma tHcy as well as creatinine levels increase and remain high after ESWL, and this shows that in the long-term the kidney function does not return to baseline. The patients included in our study were first-time ESWL patients. High tHcy levels should be taken into consideration especially in patients who underwent ESWL more than once. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Vanizor Kural B, Orem A, Cims¸ it G, Uydu HA, Yandi YE, Alver A. Plasma homocysteine and its relationships with atherothrombotic markers in psoriatic patients. Clin Chim Acta. 2003;332:23–30. 2. Tsai MY. Moderate hyperhomocysteinemia and cardiovascular disease. J Lab Clin Med. 2000;135:16–25. 3. Willis LR, Evan AP, Connors BA, Reed G, Fineberg NS, Lingeman JA. Effects of extracorporeal shock wave lithotripsy to one kidney on bilateral glomerular filtration rate and PAH clearance in minipigs. J Urol. 1996;156:1502–6. 4. Vlajkovic´ M, Slavkovic´ A, Radovanovic´ M, Siric´ Z, Stefanovic´ V, Perovic´ S. Long-term functional outcome of kidneys in children with urolithiasis after ESWL treatment. Eur J Pediatr Surg. 2002;12:118–23. 5. Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Lab Invest. 1996;56:41–6. 6. Strohmaier WL, Bichler KH, Deetjen P, Kleinknecht S, Pedro M, Wilbert DM. Damaging effects of high energy shock waves on cultured Madin Darby canine kidney (MDCK) cells. Urol Res. 1990;18:255–8. 7. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049–57. 8. Wollesen F, Brattstro¨m L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int. 1999;55:1028–35. 9. Tsai MY, Aras O, Sozen H, Hanson NQ, Woll PS, Arends VL, Hunninghake DB, Matas AJ. Plasma homocysteine levels in living kidney donors before and after uninephrectomy. J Lab Clin Med. 2004;143:340–3.
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