Acute Renal Injury Following Extracorporeal Shock Wave Lithotripsy for Urolithiasis
Ezzuldein Khalaf *
*Correspondence to: Ezzuldein Khalaf. Departments of Urology, Mafraq Hospital, Abu Dhabi, United Arab Emirates.
© 2020 Ezzuldein Khalaf. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 09 September 2020
Published: 01 October 2020
Abstract
Introduction: Extracorporeal shock wave lithotripsy is an established non-invasive treatment for selected renal and ureteric calculi. Although clinically significant acute kidney injury is uncommon, shock waves can produce vascular, tubular and inflammatory injury that may not be detected promptly by serum creatinine. Urinary biomarkers have therefore been investigated as early indicators of subclinical renal damage.
Methods: A structured evidence review was developed around PRISMA 2020 principles. Human studies and major reviews evaluating urinary or plasma biomarkers before and after extracorporeal shock wave lithotripsy were considered. Evidence was organised by biological compartment, sampling time and procedural exposure. Particular attention was given to neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18, cystatin C, beta-2 microglobulin, N-acetyl-beta-D-glucosaminidase, albumin and inflammatory cytokines. Previously published results are reported with attribution and are not presented as a new statistical meta-analysis.
Results: Most studies demonstrate biochemical evidence of transient tubular or inflammatory stress after lithotripsy, but the direction and magnitude of change vary. Urinary NGAL may rise within hours and has shown marked post-treatment increases in some cohorts, whereas other trials found no significant change. Beta-2 microglobulin and N-acetyl-beta-D-glucosaminidase frequently increase transiently, supporting proximal tubular injury. IL-18, KIM-1 and cystatin C are promising but have been examined in relatively small, heterogeneous samples. Conventional serum creatinine often remains unchanged. Comparability is limited by differences in lithotripter type, voltage strategy, shock number, stone location, baseline kidney function, hydration, assay platform, urine-creatinine normalisation and sampling schedule.
Conclusion: Urinary biomarkers can detect biological renal stress after lithotripsy earlier than serum creatinine, but no marker currently has sufficient standardisation or outcome validation for routine post-ESWL surveillance. A multimarker panel combining tubular, inflammatory and filtration markers, measured at prespecified early and recovery time points, is more promising than reliance on a single analyte.
Keywords: acute kidney injury; biomarkers; extracorporeal shock wave lithotripsy; kidney injury molecule-1; neutrophil gelatinase-associated lipocalin; urolithiasis; urinary biomarkers.
Introduction
Extracorporeal shock wave lithotripsy (ESWL), also termed shock wave lithotripsy, fragments urinary calculi by transmitting externally generated acoustic energy through tissue to the stone. Its non-invasive nature, outpatient feasibility and established effectiveness have preserved an important role in the management of selected renal and ureteric stones. Treatment is nevertheless not biologically inert. Shock waves can damage small vessels, tubular epithelium and interstitial tissue through direct mechanical stress, cavitation, shear forces, haemorrhage, vasoconstriction and ischaemia-reperfusion injury [1-4].
The clinical spectrum ranges from microscopic haematuria and transient biochemical disturbance to renal haematoma, obstruction, infection and, rarely, clinically apparent acute kidney injury. Serum creatinine and estimated glomerular filtration rate are insensitive to focal, early or mild injury because they reflect global filtration and may not change until functional reserve has been exceeded. This has stimulated interest in biomarkers released during tubular stress, epithelial injury, inflammation or altered low-molecular-weight protein handling [5-8].
A 2018 review found that urinary biomarker studies were small and inconclusive, and a 2025 systematic review again highlighted NGAL, cystatin C, KIM-1 and IL-18 while identifying major heterogeneity in protocols and sampling [8,9]. A fresh contribution must therefore move beyond listing markers. This review interprets biomarkers by biological function and time course, identifies procedural and analytical sources of variation, and proposes a standardised framework for future studies.
Methods
Review question and eligibility
The review addressed adults or children undergoing ESWL for renal or ureteric urolithiasis. Eligible evidence included prospective cohorts, controlled clinical studies, randomised comparisons and systematic or mechanistic reviews that measured a renal-injury biomarker before and after treatment. Biomarkers could be measured in urine or blood, but the principal focus was urinary detection of glomerular, proximal tubular, distal tubular or inflammatory injury. Animal studies were used only to explain mechanism or procedural protection and were not treated as direct clinical-effect evidence.
Evidence identification and appraisal
Search concepts combined terms for extracorporeal shock wave lithotripsy or shock wave lithotripsy with acute kidney injury, renal damage, oxidative stress, inflammation and individual biomarkers. Reference lists of key reviews and eligible clinical studies were examined. Evidence was appraised according to population selection, baseline renal function, stone location and burden, lithotripter and treatment protocol, comparator design, sample timing, urine dilution correction, assay method, blinding, completeness of follow-up and reporting of clinical outcomes. Because a new study-level statistical dataset was not assembled, heterogeneous biomarker concentrations were not pooled and no novel summary effect is claimed.
Mechanisms of renal injury after lithotripsy
Mechanical and vascular injury
Shock waves generate compressive and tensile forces. Cavitation bubbles expand and collapse, amplifying local shear stress and injuring capillaries and tubular structures. Experimental studies demonstrate focal haemorrhage, vascular rupture and nephron injury within the acoustic field. The extent of damage depends on peak pressure, pulse characteristics, number and rate of shocks, focal zone, coupling and renal volume exposed [2-4,10].
Ischaemia oxidative stress and inflammation
Regional vasoconstriction and microvascular damage can reduce perfusion beyond the immediate focal zone. Subsequent reperfusion generates reactive oxygen species, activates nuclear factor kappa B signalling and promotes cytokine release. TNF-alpha, IL-1 and IL-6 have been studied as indicators of the inflammatory response, although human urinary results are inconsistent [11-14]. These mechanisms explain why biomarker changes may occur in both the treated kidney and systemically, and why injury may evolve after the procedure has ended.
Tubular epithelial response
Proximal tubular cells reabsorb filtered low-molecular-weight proteins and express injury-response molecules following ischaemic or toxic stress. Increased urinary beta-2 microglobulin, N-acetyl-beta-D-glucosaminidase (NAG) and KIM-1 therefore indicates altered proximal tubular integrity or function. NGAL may arise from injured distal nephron segments, filtered systemic NGAL and activated neutrophils. These overlapping sources improve sensitivity but reduce specificity.
Biomarker specific evidence
NGAL is rapidly induced following tubular stress and can increase before serum creatinine. Its early kinetics make it attractive for post-ESWL monitoring. Zekey and colleagues evaluated NGAL after lithotripsy but did not find significant group-level changes across follow-up, including analyses by delivered shock energy [15]. A prospective randomised study comparing shock-wave protocols similarly found no significant difference in urinary NGAL [16]. In contrast, Miliši? and colleagues reported a pronounced increase in urinary NGAL, peaking around 12 hours after treatment, with associations between biomarker response and renal functional measures [17]. Vittori and colleagues also reported an early post-treatment rise [18].
These divergent results may reflect sampling time, assay sensitivity, baseline stone-related inflammation, urinary infection, hydration and treatment exposure. An isolated NGAL concentration is also affected by urine dilution; reporting a urine NGAL-to-creatinine ratio may improve comparability but introduces error when creatinine excretion is unstable.
NGAL is best viewed as a sensitive stress marker whose clinical specificity must be improved through exclusion of infection and combination with other renal markers.
KIM-1 is expressed on the apical membrane of dedifferentiated proximal tubular epithelial cells after injury and is shed into urine. It is more closely linked to proximal tubular structural injury than to glomerular filtration. Human ESWL evidence remains limited. Some studies show increased KIM-1 or associations with treatment intensity, whereas others report minimal change. Its response may be delayed compared with NGAL, so studies sampling only immediately after ESWL may underestimate its value [9,19].
IL-18 is produced by tubular epithelial and immune cells during inflammatory injury. Studies of unilateral lithotripsy have evaluated IL-18 with NGAL and cystatin C, suggesting that IL-18 can identify an inflammatory component not captured by serum creatinine [20]. Diagnostic performance has appeared strong in selected small studies, but thresholds have not been externally validated. Urinary TNF-alpha, IL-1alpha and IL-6 have also been evaluated. Goktas and colleagues found biomarker changes after ESWL, but other investigations reported no consistent urinary TNF-alpha response [11,12]. Cytokine concentrations are susceptible to infection, stone-related inflammation and sample handling.
Cystatin C is produced at a relatively constant rate, freely filtered and normally reabsorbed and catabolised in proximal tubules. Serum cystatin C reflects filtration, whereas urinary cystatin C suggests impaired proximal tubular reabsorption. After unilateral lithotripsy, cystatin C has been studied alongside NGAL and IL-18 [20]. It may detect subtle functional change when creatinine remains stable, but extra-renal determinants of serum cystatin C and limited clinical sample sizes restrict interpretation.
Beta-2 microglobulin is freely filtered and almost completely reabsorbed by the proximal tubule. Nasseh and colleagues studied 91 patients and reported an immediate 167% increase in urinary beta-2 microglobulin after ESWL [21]. A paediatric study also demonstrated a significant transient rise [22]. The marker is biologically plausible but pre-analytical stability is problematic because beta-2 microglobulin degrades in acidic urine. Prompt processing or pH control is therefore essential.
NAG is a lysosomal enzyme too large for glomerular filtration; increased urinary activity generally reflects proximal tubular cell injury. Early clinical studies demonstrated increased NAG after ESWL, sometimes together with urinary calbindin-D, a marker linked to distal tubular injury [23-25]. These markers helped establish the concept of subclinical tubular damage but are less frequently used in contemporary AKI research, partly because assay standardisation and clinically meaningful cut-offs remain limited.
Transient albuminuria, proteinuria and haematuria are common after lithotripsy and may reflect glomerular permeability, vascular trauma or urinary tract bleeding. They are inexpensive but nonspecific. Serum creatinine frequently remains unchanged during short follow-up, illustrating why a normal conventional profile does not exclude focal tubular stress. Conversely, a biomarker rise without a creatinine change should not automatically be labelled clinical AKI; it may represent subclinical injury of uncertain prognostic importance.
Comparative interpretation of biomarkers
|
Marker |
Biological signal |
Likely window |
Strength |
Main limitation |
|
NGAL |
Tubular stress; distal nephron and systemic sources |
2-12 h |
Rapid and widely studied |
Affected by infection, inflammation and urine dilution |
|
KIM-1 |
Proximal tubular structural injury |
Hours to days |
Biologically specific for injured proximal epithelium |
Limited ESWL cohorts; timing not standardised |
|
IL-18 |
Tubular and immune inflammation |
Early hours |
Captures inflammatory pathway |
Infection and systemic inflammation reduce specificity |
|
Cystatin C |
Filtration in serum; proximal reabsorption in urine |
Hours to days |
More sensitive than creatinine in some settings |
Serum level has extra-renal determinants |
|
Beta-2 microglobulin |
Proximal tubular reabsorption |
Immediate to days |
Sensitive to subtle tubular dysfunction |
Unstable in acidic urine |
|
NAG |
Proximal tubular lysosomal injury |
Hours to days |
Not filtered; supports tubular origin |
Older assays and uncertain clinical thresholds |
|
Albumin or protein |
Glomerular or vascular permeability |
Immediate |
Low cost and accessible |
Nonspecific; confounded by haematuria |
Sources of heterogeneity
Treatment related factors
Lithotripter generation, focal-zone geometry, coupling quality, voltage, shock number and delivery rate can alter tissue exposure. Experimental and clinical evidence supports protective strategies such as low-energy pretreatment, gradual voltage ramping and slower shock delivery [26-28]. Renal pelvic and calyceal stones expose renal parenchyma differently from ureteric stones. Repeated sessions, bilateral treatment or a solitary kidney may also modify risk.
Patient and stone related factors
Age, hypertension, diabetes, obesity, baseline chronic kidney disease, urinary infection, anticoagulant exposure and renal anatomy affect susceptibility. Stone obstruction itself can elevate tubular biomarkers before treatment. Without a carefully matched untreated or alternative-treatment control, the observed biomarker trajectory may reflect relief of obstruction, instrumentation or infection rather than shock-wave injury alone.
Analytical and timing factors
Published studies sample immediately after ESWL, at 2-4 hours, 6-12 hours, 24 hours, several days or weeks. A single time point can miss a short-lived peak or delayed epithelial response. Assays vary in calibration and detection limits, and results are reported as absolute concentration, change from baseline or analyte-to-creatinine ratio. These differences make an overall pooled mean difference clinically difficult to interpret even when statistical conversion is possible.
Clinical implications
Routine measurement of novel urinary biomarkers after uncomplicated ESWL is not currently supported. Most detected changes are transient, clinical AKI is uncommon and validated action thresholds are lacking. Conventional assessment remains appropriate: symptoms, urine output, haemodynamic status, haematuria, infection, obstruction and serum kidney function should guide care. Imaging is indicated when complications are suspected.
Biomarker testing may be valuable in research and selected high-risk contexts, including solitary kidneys, pre-existing chronic kidney disease, repeated or bilateral treatment, high shock burden or suspected occult injury. A panel is preferable to one marker: early NGAL for stress, KIM-1 or NAG for proximal structural injury, IL-18 for inflammation and serum or urinary cystatin C for functional context. Results should always be interpreted alongside baseline values, urinary infection testing and treatment parameters.
Proposed framework for future studies
Future trials should prospectively register protocols, use a clearly defined primary biomarker and include a comparator such as ureteroscopy, observation or an alternative lithotripsy protocol. Baseline sampling should occur after infection exclusion and before treatment. A practical minimum schedule is baseline, 2-4 hours, 12 hours, 24 hours and 7 days, with longer follow-up when persistent injury is a concern. Both absolute concentration and urine-creatinine-normalised values should be reported.
Investigators should document lithotripter model, stone size and location, number of shocks, maximum energy, shock rate, ramping, pauses, coupling, analgesia, hydration and number of sessions. Clinical outcomes should include KDIGO-defined AKI, eGFR, haematoma, obstruction, infection, readmission and long-term renal function. Statistical plans should account for repeated measures, skewed biomarker distributions, baseline imbalance and multiplicity. Diagnostic studies require prespecified thresholds and external validation rather than post hoc selection of the best-performing cut-off.
Strengths and limitations
The biomarker literature provides coherent biological evidence that ESWL can produce transient renal stress even when serum creatinine is unchanged. It spans tubular proteins, injury-response molecules, cytokines, oxidative-stress pathways and filtration markers. Experimental work also connects biomarker changes to known vascular and parenchymal lesions.
The clinical evidence remains limited by small samples, heterogeneous treatment protocols, variable timing, inconsistent urine normalisation and limited linkage with patient-important outcomes. Many studies lack an untreated or active comparator. Infection, obstruction and haematuria can confound urinary measurements.
The recent 2025 systematic review substantially overlaps the broad question, so the value of the present manuscript lies in biomarker kinetics, procedural modifiers and a standardised future-study framework rather than an unsupported claim of a new pooled effect.
Conclusion
ESWL can induce measurable tubular, vascular and inflammatory renal stress that is often invisible to serum creatinine. Urinary NGAL, KIM-1, IL-18, cystatin C, beta-2 microglobulin and NAG each capture different components and time points of this response. No single marker is sufficiently validated for routine clinical surveillance, and current evidence does not establish that transient biomarker elevations predict chronic kidney impairment. Standardised multimarker studies with uniform sampling, complete treatment dosimetry and long-term clinical outcomes are required before biomarker-guided modification of lithotripsy can be recommended.
Declarations
Ethics approval and consent to participate: Not applicable; this article reviews published literature.
Consent for publication: Not applicable.
Availability of data and materials: All evidence discussed is available in the cited publications.
Competing interests: The authors declare no competing interests.
Funding: No specific funding was received for this work.
Author contributions: To be completed using the CRediT taxonomy before submission.
Acknowledgements: None.
References