The Application of Kidney Injury Molecule-1 to Determine the Duration Between Shockwave Lithotripsy Sessions

Abstract

Purpose:

We aimed to evaluate the role of kidney injury molecule-1 (KIM-1) in determining the intervals between shockwave lithotripsy (SWL) sessions.

Patients and Methods:

This was a prospective, controlled study. It included 40 patients with unilateral kidney stones and 40 healthy persons of a similar age group as controls. The patients' midflow urine samples were collected before SWL and 1 hour, 1 day, 1 week, and 1 month after the procedure.

Results:

The average age in the SWL and control groups was 45 ± 14 and 39 ± 15 years, respectively (P = 0.336). The average KIM-1 value before SWL was 0.74 ± 0.35 ng/mL, which was significantly higher than that of the control group (0.51 ± 0.14 ng/mL) (P < 0.001). Similarly, the average values of the urine samples after SWL were higher than those of the control group (P < 0.001). When the KIM-1 values of the patients given SWL were compared within the group, the KIM-1 values 1 hour (1.06 ± 0.51) and 1 day (0.99 ± 0.67) after the procedure were statistically clearly higher than those before the procedure (P < 0.001) and statistically clearly higher than those of the control group (P = 0.005). The KIM-1 values 1 week and 1 month after the procedure were not significantly different than the preprocedure values (P = 0.652 and P = 0.747, respectively).

Conclusion:

KIM-1 is a noninvasive biomarker that may be used to show renal damage because of stones and early-stage renal damage linked to SWL. In addition, post-SWL KIM-1 values may be used to determine the interval between SWL sessions.

Introduction

The introduction of shockwave lithotripsy (SWL) in the early 1980s marked an important change in treatment strategies for kidney stones. Its success varied, depending on the device, patient, and properties of the stones.¹ Today, SWL, which is a less invasive treatment modality than percutaneous nephrolithotomy and retrograde intrarenal surgery, is considered the best option for kidney stones smaller than 2 cm and lower pole stones smaller than 1.5 cm^1,2 Despite its various advantages, SWL also carries a range of risks. These include inflammation after treatment, vein damage, ischemia, and hemorrhage, which may cause acute kidney damage, including scarring.³

Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein released in response to renal proximal tubule damage, and it is a sensitive and specific biomarker of renal damage.⁴ Many studies have shown that it is released at high rates from proximal tubule cells in various diseases, such as heart failure, kidney cell carcinoma, vesicoureteral reflux (VUR), and IgA nephropathy.^5,6 Another study discovered a correlation between increased KIM levels and the severity of renal damage.⁷ Studies of the effects of SWL on the kidney reported that it resulted in no significant changes in a range of parameters, including electrolytes, such as serum creatinine (Cr), calcium, and chlorine.^8,9

The search for more efficient and reliable biomarkers of kidney damage has identified a variety of candidates, such as intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin (IL)-18, neutrophil gelatinase associated lipocalin (NGAL), and KIM-1.^3,10 Of these, KIM-1 can be applied easily to show early kidney damage and is considered promising because it is noninvasive.

In this study, we used KIM-1 to determine acute kidney damage after SWL and identified when the renal damage caused by SWL was resolved to study the role of KIM-1 in determining the intervals between SWL sessions.

Patients and Methods

This was a prospective, controlled study. It included 40 patients with unilateral kidney stones and 40 healthy men and women of a similar age group as controls. All the subjects gave written consent. The study was conducted between February and June 2014. Before the study, the kidney functions of all the patients were checked, and those with chronic disease affecting kidney function, a history of kidney surgery, single kidneys, a history of kidney tumors, congenital anomalies, or nephrotoxic medications were excluded.

Of the patients who underwent SWL for kidney stones, cases with first treatment (surgical, SWL) in only one kidney and a single stone were chosen. In all cases, the SWL was performed in a single session on a single kidney using the same electro-hydraulic type device (Multimed Classic, ELMED Lithotripsy Co., Turkey). All the patients lay in a supine position. A nonsteroidal anti-inflammatory drug was administered intramuscularly 30 minutes before the SWL procedure. The frequency of the SWL was 1 Hz, and each patient received a mean of 2825 shocks. The force of the shocks began at 12 kV and rose in stages during the first 500 shocks to reach 18.5 kV. Demographic data, including age, sex, Cr levels, and body mass index (BMI), were recorded, and the stone size, side, number of shocks, energy, and frequency of SWL given were noted.

Midflow urine samples were collected from the patients before the SWL procedure and 1 hour, 1 day, 1 week, and 1 month after the procedure. The samples were centrifuged, and the supernatant was separated and stored at −20°C. KIM-1 values were determined using the enzyme-linked immunosorbent assay method (SunRed Biological Technology, Shanghai).

Statistical evaluation was performed using IBM SPSS 17.0 (SPSS, Inc., Chicago, IL). Normality was investigated with the Shapiro-Wilk test. To compare data with a normal distribution, an independent two-sample t test was used, and the Mann–Whitney U test was used for data without a normal distribution. The relationship between variables was investigated with the Spearman correlation analysis. Comparison of the data within groups was completed with a two-way analysis of variance and the Tukey honest significant difference test. The results are presented as the arithmetic mean ± standard deviation and median (min-max). The level of significance was accepted as P < 0.05.

Results

Of the SWL group of 40 patients, 27 were male, and 13 were female, whereas in the control group of 40 patients, 28 were male, and 12 were female (P = 0.424). The average age in the SWL and control groups was 45 ± 14 and 39 ± 15 years, respectively, with no significant between-group differences (P = 0.336). Similarly, there was no difference in the BMI and Cr values of the control and SWL groups (P = 0.168 and P = 0.371, respectively). SWL was applied to the right and left kidneys of 24 and 16 patients, respectively. The average stone size was 0.98 ± 0.43 mm. The patients were subjected to an average of 2825 shock waves, and the average energy was 18.8 kV (Table 1). None of the patients had any major complications, such as hemorrhage, complicated urinary tract infections, hematomas, or obstructions, during or after the procedure.

Table 1.

Characteristics of the Groups

	SWL group	Control group	P
N	40	40
Mean age (years)	45 ± 14	39 ± 15	0.336
Male/female	27/13	28/12	0.424
BMI	27.6 ± 3.7	26.5 ± 3.7	0.168
Cr levels	0.9 (0.5–4.9)	0.9 (0.6–1.1)	0.371
Mean stone size (mm)	0.98 ± 0.43	-
Laterality (right/left)	24/16	-
Mean shock	2825	-
Mean kV	18.8	-

SWL = shockwave lithotripsy; BMI = body mass index; Cr = creatinine; P = level of significance.

The average KIM-1 value before the SWL procedure was 0.74 ± 0.35 ng/mL, which was significantly higher than that of the control group (0.51 ± 0.14 ng/mL) (P < 0.001). Similarly, the average post-SWL value of the four urine samples was higher than that of the control group (P < 0.001) (Table 2). When the KIM-1 values of the SWL group were compared within the group, the KIM-1 values 1 hour (1.06 ± 0.51) and 1 day (0.99 ± 0.67) after the procedure were statistically clearly higher than those before the procedure (P < 0.001) and statistically clearly higher than those of the control group (P = 0.005). The KIM-1 values 1 week and 1 month after the procedure were not significantly different from those before the procedure (P = 0.652 and P = 0.747, respectively).

Table 2.

The Average Kidney Injury Molecule-1 Values in the Control Group and Shockwave Lithotripsy

		SWL group
	Control group	Before	1st hour	1st day	1st week	1st month	P value
KIM-1 (ng/mL)	0.51 ± 0.14	0.74 ± 0.35	1.06 ± 0.51	0.99 ± 0.67	0.83 ± 0.41	0.83 ± 0.41	<0.05

When the relationship between KIM-1 values and age, sex, laterality, Cr values, BMI, stone size, energy, and the number of shocks was investigated, there was no correlation between those parameters and KIM-1 values (Tables 3, 4).

Table 3.

Correlation Between Kidney Injury Molecule-1 and Other Parameters

	r	P
Age	0.120	0.462
BMI	0.252	0.117
Cr	0.092	0.572
Stone size	0.085	0.601
Energy (kV)	0.157	0.334
Shocks	−0.216	0.180

r = correlation coefficient.

Table 4.

Correlation of Kidney Injury Molecule-1 KIM-1 with Sex and Laterality

	E1 (median [min-max])	P value
Sex
M	0.64 (0.19–1.62)	0.732
F	0.60 (0.16–1.32)
Laterality
Right	0.56 (0.19–1.62)	0.557
Left	0.67 (0.16–1.26)

Discussion

Renal stone disease is a frequent and important health problem.¹¹ Invasive treatment methods were previously widely used to resolve this problem. In the last 30 years, the introduction of noninvasive SWL has offered a new approach to the management of stones. Recent clinical and experimental studies, however, have challenged the opinion that SWL does not damage renal and surrounding tissues, with a range of early and late side effects revealed thanks to developments in technology and research.

One study showed that because of changes in renal perfusion that occurred during SWL, ischemia/reperfusion damage occurred.¹² Other studies demonstrated that free oxygen radicals increased in renal tissue and that the total antioxidant capacity declined as a result of ischemia/reperfusion damage.^13,14 Kidneys are a well-perfused organ; as a result, SWL renal blood flow and blood cells in the kidney are affected. A study of renal blood flow using gadolinium-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging found that cortical blood flow was reduced after SWL.¹⁵ Another study evaluated intrarenal blood flow changes using Doppler ultrasound and observed increased resistive index and pulsatility index values after SWL.¹⁶ In addition, studies revealed that erythrocyte glucose-6-phosphate dehydrogenase and superoxide dismutase functions fell significantly and that erythrocyte membrane defects developed after SWL.^12,17

Since KIM-1 was discovered in 1998, various human and experimental animal studies have demonstrated its role as a specific and sensitive biomarker of renal proximal tubule damage.^18
–20 It is assumed that KIM-1 is released by endogenous phagocytes on the surface of epithelial cells in the damaged kidney. Interestingly, as KIM-1 is a specific marker that is released only from apoptotic tubular epithelial cells, it can be identified in urine immediately after acute kidney damage.^7,21

When renal proximal tubule cells are damaged, a variety of molecules are released.^22,23 KIM-1, IL-18, IL-6, NGAL, intercellular adhesion molecule-1, and β2-microglobulin are some of the molecules used to diagnose and monitor this damage.^3,10,22,24 KIM-1 appears to be the most useful of these markers for showing kidney damage. In an experimental animal study, Zhou and associates²⁵ compared KIM-1 and other markers to examine kidney damage in rats given nephrotoxic agents and found that KIM-1 was a more specific and sensitive marker than other biomarkers. Similarly, in an animal model of ischemia/reperfusion damage with early-stage renal damage, detected by a significant fall in Cr clearance and a significant increase in proteinuria, KIM-1 increased five-fold.⁷ Increased KIM-1 values were also reported to be related to the severity of kidney damage.²⁶

Many studies have shown that KIM-1 may increase in a variety of renal pathologies. For example, Legrand and Gayat²⁷ reported that increases in KIM-1 may be a marker of renal damage linked to circulation insufficiency. Seo colleagues⁶ showed that KIM-1 increased in IgA nephropathy, a glomerular disease, and that KIM-1 values returned to normal after treatment of the disease. KIM-1 levels were also found to be an independent predictor of kidney failure and linked to the final stages of this disease.²⁸

We detected significantly higher KIM-1 values in the early post-SWL period compared with the pre-SWL period. This finding is similar to that of Hatipoglu and coworkers¹³ who used KIM-1 values to evaluate kidney damage after SWL. Unlike their study, we found that the KIM-1 values of the patient group before the SWL procedure were higher than those of the control group. We attributed this finding to renal damage caused by the stone itself or metabolic disturbances, such as hyperoxaluria or hypercalcemia, as revealed by some studies.^29,30 In addition, Hatipoglu and associates¹³ only evaluated the effect of kidney damage in the early period after SWL. In contrast, we evaluated KIM-1 values 1 day, 1 week, and 1 month after the procedure. We found that the KIM-1 values on day 1 were significantly high, similar to those at 1 hour. Furthermore, we detected no difference in the 1-week and 1-month KIM-1 values compared with the preprocedure values.

In the guidelines, there is no consensus on the frequency with which SWL sessions should be repeated. The damage risk of treatments for kidney stones are the clearest, and shorter duration (1-day intervals) between treatment sessions for ureter stones is accepted by the majority.³¹ Based on studies showing that healing of contusions in renal tissue takes ∼2 weeks, a 10 to 14 day wait between consecutive SWL sessions has been recommended.³²

This information, however, is limited to clinical experience. In our study, although the KIM-1 values on day 1 after the SWL procedure were high compared with the preprocedure values, the values 1 week later were similar to the preprocedure values. These data indicate that the kidney damage resolved in 1 week after the SWL, and they demonstrate the usefulness of KIM-1 values in determining the intervals between SWL sessions.

According to estimates of the World Health Organization, 1.7 billion people are overweight and obese worldwide. Obesity and metabolic syndrome are significant contributing factors to urolithiasis.³³ In the present study, we investigated the relationship between BMI and KIM-1 values. We found no correlation between the two parameters. Similarly, we detected no relationship between KIM-1 values and age, sex, Cr values, laterality, stone size, energy, and the number of shocks.

KIM-1 values are used in other areas of urology. For example, increases in KIM-1 values in clear-cell and papillary renal -ell carcinoma may be used as a predictor of the malignancy risk of renal masses in preoperative evaluations.⁵ They are also used in patients with VUR. As the grade of VUR increases, KIM-1 levels increase, and these have been shown to have a potential role in determining severe scarring.³⁴ KIM-1 levels are also used to determine renal damage in transplanted kidneys and nephron-sparing surgery, as well as damage from nephrotoxic agents.^20,24,25 Research has suggested that SWL may cause diabetes mellitus and hypertension.³⁵ Studies are needed to determine whether KIM-1 could be used to predict in which patients diabetes mellitus or hypertension might develop after SWL.

Previous studies indicated that KIM-1was a marker of renal damage in a variety of renal pathologies. Our study showed that it also appears to be a potential noninvasive biomarker of renal damage caused by SWL. Although previous research demonstrated the role of KIM-1 in determining kidney damage after SWL, no study examined KIM-1 values 1 day, 1 week, and 1 month after SWL. We also examined the resolution of kidney damage after SWL and the role of KIM-1 in determining the intervals between SWL sessions. To clearly determine these effects, more advanced studies with a variety of biomarkers are needed. The limitations of our study are not comparing KIM-1 levels with the glomerular filtration rate, Cr clearance, and other oxidative stress markers.

Conclusion

KIM-1 is a noninvasive biomarker that may be used to show renal damage from stones and early-stage renal damage linked to SWL. In addition, post-SWL KIM-1 values may be used to determine the interval between SWL sessions.

Footnotes

Acknowledgment

We gratefully acknowledge expert statistician Kürşat Yurdakoş who evaluated our study data.

Author Disclosure Statement

We accepted financial support from Samsun Training and Research Hospitals' Training and Research Foundation for analysis of the KIM-1 levels in this study.

Abbreviations Used

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