Simultaneous determination of multiple urine biomarkers for kidney injury using SPE combined with LC-MS/MS.

BACKGROUND AND OBJECTIVES: Urinary biomarkers such as low molecular weight proteins and small molecular weight metabolites are crucial in the diagnosis of kidney injury. The objective of this study was to develop and preliminarily validate a sensitive and specific method using solid-phase extraction (SPE) in conjunction with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous measurement of these biomarkers in human urine. METHOD: This study presents the development of a solid-phase extraction method integrated with LC-MS/MS analyzing biomarkers including creatinine, urea, ß2-microglobulin, α1-microglobulin, and cystatin C in human urine. An enhanced solid-phase cartridge technique was employed for peptide purification and dilution of small molecule metabolites during sample preparation. RESULTS: The developed LC-MS/MS method achieved satisfactory separation of the five analytes within 15 min. Accuracy levels ranged from -8.6% to 13.6%. Both intra-assay and inter-assay imprecision rates were maintained below 7.9% for all analytes. CONCLUSIONS: The established LC-MS/MS method effectively quantifies creatinine, urea, ß2-microglobulin, α1-microglobulin and cystatin C concurrently. This offers a viable alternative for the detection of kidney injury biomarkers in human urine, demonstrating potential for clinical application in kidney injury diagnosis.

Zoledronic acid and ibandronate-induced nephrotoxicity in 2D and 3D proximal tubule cells derived from human and rat.

Drug-induced proximal tubule (PT) injury remains a serious safety concern throughout drug development. Traditional in vitro 2-dimensional (2D) and preclinical in vivo models often fail to predict drug-related injuries presented in clinical trials. Various 3-dimensional (3D) microphysiological systems (MPSs) have been developed to mimic physiologically relevant properties, enabling them to be more predictive toward nephrotoxicity. To explore the capabilities of an MPS across species, we compared cytotoxicity in hRPTEC/TERT1s and rat primary proximal tubular epithelial cells (rPPTECs) following exposure to zoledronic acid and ibandronate (62.5-500 µM), and antibiotic polymyxin B (PMB) (50 and 250 µM, respectively). For comparison, we investigated cytotoxicity using 2D cultured hRPTEC/TERT1s and rPPTECs following exposure to the same drugs, including overlapping concentrations, as their 3D counterparts. Regardless of the in vitro model, bisphosphonate-exposed rPPTECs exhibited cytotoxicity quicker than hRPTEC/TERT1s. PMB was less sensitive toward nephrotoxicity in rPPTECs than hRPTEC/TERT1s, demonstrating differences in species sensitivity within both 3D and 2D models. Generally, 2D cultured cells experienced faster drug-induced cytotoxicity compared to the MPSs, suggesting that MPSs can be advantageous for longer-term drug-exposure studies, if warranted. Furthermore, ibandronate-exposed hRPTEC/TERT1s and rPPTECs produced higher levels of inflammatory and kidney injury biomarkers compared to zoledronic acid, indicating that ibandronate induces acute kidney injury, but also a potential protective response since ibandronate is less toxic than zoledronic acid. Our study suggests that the MPS model can be used for preclinical screening of compounds prior to animal studies and human clinical trials.

Recent ambient temperature and fine particulate matter (PM2.5) exposure is associated with urinary kidney injury biomarkers in children.

BACKGROUND: Limited research has examined associations between exposure to ambient temperature, air pollution, and kidney function or injury during the preadolescent period. We examined associations between exposure to ambient temperature and particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) with preadolescent estimated glomerular filtration rate (eGFR) and urinary kidney injury biomarkers. METHODS: Participants included 437 children without cardiovascular or kidney disease enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors birth cohort study in Mexico City. eGFR and urinary kidney injury biomarkers were assessed at 8-12 years. Validated satellite-based spatio-temporal models were used to estimate mean daily temperature and PM2.5 levels at each participant's residence 7- and 30-days prior to the date of visit. Linear regression and distributed lag nonlinear models (DLNM) were used to examine associations between daily mean temperature and PM2.5 exposure and kidney outcomes, adjusted for covariates. RESULTS: In single linear regressions, higher seven-day average PM2.5 was associated with higher urinary alpha-1-microglobulin and eGFR. In DLNM analyses, higher temperature exposure in the seven days prior to date of visit was associated with a decrease in urinary cystatin C of -0.56 ng/mL (95 % confidence interval (CI): -1.08, -0.04) and in osteopontin of -0.08 ng/mL (95 % CI: -0.15, -0.001). PM2.5 exposure over the seven days prior to date of visit was associated with an increase in eGFR of 1.77 mL/min/1.73m2 (95 % CI: 0.55, 2.99) and urinary cystatin C of 0.19 ng/mL (95 % CI: 0.03, 0.35). CONCLUSIONS: Recent exposure to ambient temperature and PM2.5 were associated with increased and decreased urinary kidney injury biomarkers that may reflect subclinical glomerular or tubular injury in children. Further research is required to assess environmental exposures and worsening subclinical kidney injury across development.

Cardiac Surgery-Associated Acute Kidney Injury in Adults: Clinical Outcomes, Prevention Strategies, and Future Therapies in the Postoperative Period.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major postoperative complication that results in significant morbidity and mortality. Causes are heterogeneous, treatment strategies are largely supportive, and data on outcomes, such as potential for recovery, are lacking. This literature review explores the evidence on how furosemide may alter the course and outcome of postoperative fluid overload in patients with CSA-AKI. Nephrology nurse practitioners need to employ tailored preventive therapies at the preoperative, intraoperative, and postoperative points of care. This article discusses the unique methods for CSA-AKI mechanisms, hemodynamic monitoring strategies employed at the point of care recommended by clinical practice guidelines and recent evidence, and emerging biomarkers of AKI.

Iohexol-Measured Glomerular Filtration Rate and Urinary Biomarker Changes between Vancomycin and Vancomycin Plus Piperacillin-Tazobactam in a Translational Rat Model.

Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination. Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 h. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated with the urinary biomarkers kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to the control, rats that received vancomycin had numerically lower GFRs after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin plus piperacillin-tazobactam (vancomycin+piperacillin-tazobactam) did not exhibit worse kidney function or injury biomarkers than rats receiving vancomycin alone. The combination of vancomycin and piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.

Effect of the Ureteral Access Sheath Size on Acute Kidney Injury Biomarkers in Retrograde Intrarenal Surgery: A Prospective, Randomized Study.

INTRODUCTION: The aim of the study was to investigate the effect of the diameter of the ureteral access sheath (UAS) used during RIRS on kidney injury based on acute kidney injury (AKI) biomarkers. METHODS: This prospectively randomized controlled study included a total of 125 patients divided into three groups: group 1 (n = 52) in which a 12/14 Fr UAS was used, group 2 (n = 52) in which a 9.5/11.5 Fr UAS was used, and group 3 (n = 21) that was designed as the control group with no urogenital disease history. Urine samples were collected preoperatively and at the postoperative second and 24th hours after surgery and analyzed for AKI using the urinary kidney injury molecule-1 (uKIM-1), N-acetyl-ß-D-glucosaminidase, and neutrophil gelatinase-associated lipocain biomarkers. RESULTS: In group 1, there was no statistical change in any of the three AKI biomarkers at the postoperative second or 24th hour compared to the preoperative period. In group 2, the values of all three AKI biomarkers were statistically significantly increased at the postoperative second and 24th hours compared to the preoperative period while no statistical difference was observed between the two postoperative evaluation times. At the postoperative second hour, the uKIM-1 value was statistically significantly higher in group 2 compared to group 1 (p = 0.043). CONCLUSIONS: The results of our study showed that AKI was not observed in RIRS performed with a 12/14 Fr UAS while the use of a 9.5/11.5 Fr UAS resulted in AKI according to the assessment of the related biomarkers.

The Utility of Novel Kidney Injury Biomarkers in Early Detection of CSA-AKI.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most common complications of cardiac surgery procedures. In this study, the authors attempt to provide new data regarding the application of novel kidney injury biomarkers in the early diagnostics of CSA-AKI. 128 adult patients undergoing elective cardiac surgery procedures with the use of cardiopulmonary by-pass (CPB) were enrolled in this study. Novel kidney injury biomarkers were marked in the plasma and urine 6 h after weaning from the CPB. A significant difference in the postoperative biomarkers' concentration between the AKI and no-AKI group was found, regarding plasma IL-8, plasma TNF-α and urine NGAL, normalized for creatinine excretion (NGAL/Cr). These were also independent predictors of CSA-AKI. An independent risk factor for CSA-AKI proved to be preoperative CKD. Plasma IL-8 and TNF-α, as well as urine NGAL/Cr, are independent early indicators of CSA-AKI and pose a promising alternative for creatinine measurements. The cut-off points for these biomarkers proposed in this investigation should be confronted with more data and revised to achieve a suitable diagnostic value.

Reference intervals of urinary kidney injury biomarkers for middle-aged men and women determined by quantitative protein mass spectrometry.

BACKGROUND AND AIMS: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins neutrophil-gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP2), kidney injury molecule-1 (KIM-1), C-X-C motif chemokine 9 (CXCL9), transforming growth factor-beta 1 (TGF-ß1), solute carrier family 22 member 2 (SLC22A2), nephrin, cubilin, and uromodulin (UMOD) have been proposed as early kidney injury biomarkers. To guide clinical interpretation, their urinary concentrations should be accompanied by reference intervals, which we here establish in a representative Dutch middle-aged population. MATERIALS AND METHODS: The 24 h urine samples from 1443 Caucasian middle-aged men and women were analyzed for the biomarkers by quantitative LC-MS/MS. Biomarker excretion per 24 h were calculated, and urine creatinine and osmolality were measured for dilution normalization. This population was characterized by demographic and anthropometric parameters, comorbid conditions, and conventional kidney function measures. RESULTS: NGAL, IGFBP7, TIMP2, KIM-1, and UMOD could be quantified in this population, whereas nephrin, SLC22A2, and CXCL9 were below their detection limits. Urine creatinine and osmolality were correlated to urine volume (r = -0.71; -0.74) and to IGFBP7 (r = 0.73; 0.71) and TIMP2 (r = 0.71; 0.69). Crude and normalized biomarker concentrations were affected by sex, but not by age, body mass index, smoking, kidney function, or common comorbid conditions. The reference intervals (men; women) were 18-108; 21-131 pmol IGFBP7/mmol creatinine, 1-63; 4-224 pmol NGAL/mmol creatinine, 7-48; 7-59 pmol TIMP2/mmol creatinine, <1-9; <1-12 pmol KIM-1/mmol creatinine, and 0.1-1.2; 0.1-1.7 mg UMOD/mmol creatinine. CONCLUSION: We present dilution-normalized and sex-stratified urinary reference intervals of kidney injury biomarkers in a middle-aged Caucasian population.

Assessment and Prognosis in CSA-AKI Using Novel Kidney Injury Biomarkers: A Prospective Observational Study.

BACKGROUND: There is a need for early diagnostic solutions for cardiac surgery associated acute kidney injury (CSA-AKI) as serum creatinine changes do not occur dynamically enough. Moreover, new approaches are needed for kidney protective strategy in patients undergoing cardiac surgery procedures; Methods: Samples of serum and urine were taken from the selected group of patients undergoing elective cardiac surgery procedures. The aim of this study was to assess the utility of specific inflammation and kidney injury biomarkers in the early diagnostic of CSA-AKI and in the prognosis of long-term postoperative kidney function; Results: At 6 h after weaning from cardiopulmonary bypass, there were significant differences in IL-6, IL-8, TNF-α, MMP-9 and NGAL concentrations in patients with CSA-AKI, compared to the control group. Serum IL-8 and urine NGAL 6 h after weaning from CPB proved to be independent acute kidney injury predictors. The TNF-α, MMP-9, IL-18, TIMP-1 and MMP-9/TIMP-1 ratio in the early postoperative period correlated with long-term kidney function impairment; Conclusions: Novel kidney injury biomarkers are an eligible tool for early diagnosis of CSA-AKI. They are also reliable indicators of long-term postoperative kidney function impairment risk after cardiac surgery procedures.

Nephrotoxic antisense oligonucleotide SPC5001 induces kidney injury biomarkers in a proximal tubule-on-a-chip.

Antisense oligonucleotides (ASOs) are a promising therapeutic modality. However, failure to predict acute kidney injury induced by SPC5001 ASO observed in a clinical trial suggests the need for additional preclinical models to complement the preceding animal toxicity studies. To explore the utility of in vitro systems in this space, we evaluated the induction of nephrotoxicity and kidney injury biomarkers by SPC5001 in human renal proximal tubule epithelial cells (HRPTEC), cultured in 2D, and in a recently developed kidney proximal tubule-on-a-chip. 2D HRPTEC cultures were exposed to the nephrotoxic ASO SPC5001 or the safe control ASO 556089 (0.16-40 µM) for up to 72 h, targeting PCSK9 and MALAT1, respectively. Both ASOs induced a concentration-dependent downregulation of their respective mRNA targets but cytotoxicity (determined by LDH activity) was not observed at any concentration. Next, chip-cultured HRPTEC were exposed to SPC5001 (0.5 and 5 µM) and 556089 (1 and 10 µM) for 48 h to confirm downregulation of their respective target transcripts, with 74.1 ± 5.2% for SPC5001 (5 µM) and 79.4 ± 0.8% for 556089 (10 µM). During extended exposure for up to 20 consecutive days, only SPC5001 induced cytotoxicity (at the higher concentration; 5 µM), as evaluated by LDH in the perfusate medium. Moreover, perfusate levels of biomarkers KIM-1, NGAL, clusterin, osteopontin and VEGF increased 2.5 ± 0.2-fold, 3.9 ± 0.9-fold, 2.3 ± 0.6-fold, 3.9 ± 1.7-fold and 1.9 ± 0.4-fold respectively, in response to SPC5001, generating distinct time-dependent profiles. In conclusion, target downregulation, cytotoxicity and kidney injury biomarkers were induced by the clinically nephrotoxic ASO SPC5001, demonstrating the translational potential of this kidney on-a-chip.

Biomarkers of Kidney Injury in Very-low-birth-weight Preterm Infants: Influence of Maternal and Neonatal Factors.

BACKGROUND/AIM: Acute kidney injury is an important cause of mortality in very-low-birth-weight (VLBW) preterm infants. As in the general population, the detection of renal damage cannot rely on the measurement of serum creatinine, since it has been demonstrated to be a weak predictor and a delayed indicator of kidney function deterioration. However, several candidate biomarkers have failed to prove sufficient specificity and sensitivity for a routine clinical use because of the poor awareness of their biological role. This study was aimed to investigate the impact of different maternal and neonatal conditions on several renal biomarkers in VLBW preterm infants during the first week of life. PATIENTS AND METHODS: Preterm infants<32 weeks' gestation and <1500g were enrolled. We measured urinary biomarkers kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, epidermal growth factor (EGF) and osteopontin (OPN) on the 1st, 3rd, and 7th day after birth. RESULTS: Thirty-tree infants were included. The multivariate analysis showed a significant association between gestational age, the presence of patent ductus arteriosus, antenatal maternal hypertension and the levels of urinary biomarkers. CONCLUSION: There is a possible relation between early biomarkers of renal injury and antenatal, perinatal and post-natal characteristics in VLBW preterm infants during the first week of life.

Kidney Function, Self-Reported Symptoms, and Urine Findings in Nicaraguan Sugarcane Workers.

Background: An epidemic of CKD in Central America predominantly affects males working in certain industries, including sugarcane. Urinary tract infections are commonly diagnosed among men in Nicaragua, who often receive antibiotics and nonsteroidal anti-inflammatory drugs for urinary symptoms. Methods: We followed 251 male Nicaraguan sugarcane workers in seven job tasks over one harvest and measured urine dipstick parameters, kidney injury biomarkers, and eGFR. We administered a questionnaire about urinary symptoms, health-related behaviors, and medication history. We cultured urine in a subset of workers. Results: The study population was composed of factory workers (23%), cane cutters (20%), irrigators (20%), drivers (16%), agrichemical applicators (12%), seeders/reseeders (6%), and seed cutters (4%). The mean age of participants was 33.9 years, and mean employment duration was 10.1 years. Cane cutters reported higher proportions of urinary-related symptoms compared with agrichemical applicators, irrigators, and seeders/reseeders. Seed cutters were more likely to take antibiotics (22%), whereas drivers and seeders/reseeders were more likely to take pain medications (27% and 27%, respectively). Proteinuria was uncommon, whereas dipstick leukocyte esterase was relatively common, especially among cane cutters, seed cutters, and seeders/reseeders (33%, 22%, and 21% at late harvest, respectively). Dipstick leukocyte esterase at late harvest was associated with a 12.9 ml/min per 1.73 m2 (95% CI, -18.7 to -7.0) lower mean eGFR and 2.8 times (95% CI, 1.8 to 4.3) higher mean neutrophil gelatinase-associated lipocalin. In general, workers who reported urinary-related symptoms had higher mean kidney injury biomarker levels at late harvest. None of the workers had positive urine cultures, including those reporting urinary symptoms and/or with positive leukocyte esterase results. Amoxicillin, ibuprofen, and acetaminophen were the most commonly used medications. Conclusions: Job task is associated with urinary symptoms and dipstick leukocyte esterase. Urinary tract infection is misdiagnosed based on leukocyte esterase, which may be an important predictor of kidney outcomes.

Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury.

Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or ½ LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and ½ LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol-specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI.

Urinary Kidney Injury Molecule-1 but Not Urinary Neutrophil Gelatinase Associated Lipocalin Is Increased after Short Maximal Exercise.

BACKGROUND AND AIMS: Urinary neutrophil gelatinase associated lipocalin (uNGAL) and urinary kidney injury molecule-1 (uKIM-1) are markers of acute kidney injury. The albuminuria is a well-known abnormality after physical exercise. The aim of this study was to investigate changes in uNGAL and uKIM-1 after intensive exercise causing albuminuria. METHODS: The study population consisted of 19 participants (10 males and 9 females). The mean age of participants was 35.74 years. All were fit amateur runners; the mean body mass index was 21.99 in females and 24.71 in males. The subjects underwent a graded treadmill exercise test (GXT) according to the Bruce protocol. Maximal oxygen consumption (VO2max) was measured. Immediately before and after the test urine was collected. Urinary creatinine, albumin, NGAL, and KIM-1 were measured. Albumin to creatinine (ACR), KIM-1 to creatinine (KCR), and NGAL to creatinine (NCR) ratios were calculated. RESULTS: The mean VO2max was 53.68 in females and 59.54 mL/min/kg in males. Albuminuria and ACR were significantly higher after exercise. An increase in the ACR from 8.82 to 114.35 mg/g (p < 0.01) was observed. uKIM-1 increased significantly after exercise from 849.02 to 1,243.26 pg/mL (p < 0.05). KCR increased from 1,239.1 to 1,725.9 ng/g but without statistical significance (p = 0.07). There were no statistical changes in pre- and post-run uNGAL levels. There was no correlation between post-GXT albuminuria and uKIM-1. CONCLUSIONS: uKIM-1 is a very sensitive marker of kidney dysfunction. In our study, uKIM-1 increased significantly after a very short period of exercise. It is not clear if the increase in KIM-1 is caused by post-exercise albuminuria.

Demographic data for urinary Acute Kidney Injury (AKI) marker [IGFBP7]·[TIMP2] reference range determinations.

This data in brief describes characteristics of chronic stable comorbid patients who were included in reference range studies of [IGFBP7]·[TIMP-2] "Reference Intervals of Urinary Acute Kidney Injury (AKI) Markers [IGFBP7]·[TIMP2] in Apparently Healthy Subjects and Chronic Comorbid Subjects without AKI" [1]. In order to determine the specificity of [IGFBP7]·[TIMP-2] for identifying patients at risk of developing AKI we studied a cohort with nine broad classification of disease who did not have AKI. Details regarding the population that was targeted for inclusion in the study are also described. Finally, we present data on the inclusion criteria for the healthy subjects used in this investigation to determine the reference range.

Pituitary adenylate cyclase-activating polypeptide prevents contrast-induced nephropathy in a novel mouse model.

We determined whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) prevents contrast-induced nephropathy using human renal proximal tubule epithelial (HK-2) cells and homozygous endothelial nitric oxide synthase-deficient (eNOS(-/-)) mice as a novel in vivo model. Cultured HK-2 cells were pretreated with 10(-9)-10(-6) mol/L PACAP or vasoactive intestinal peptide (VIP) for 1 h, and then exposed to ionic (Urografin) or nonionic (iohexol) contrast media at 50 mg iodine/mL for 24 h. Male eNOS(-/-) mice received Urografin (1.85 g iodine/kg) intravenously after water deprivation for 24 h, and PACAP38 (10 µg) intraperitoneally 1 h before and 12 h after Urografin injection. Urografin and iohexol increased lactate dehydrogenase and kidney injury molecule 1 in the culture medium, induced apoptosis, and inhibited cell proliferation in HK-2 cell cultures. PACAP38 and VIP reduced these changes in a dose-dependent manner. PACAP38 was more potent than VIP. In eNOS(-/-) mice, Urografin raised serum creatinine and cystatin C levels, caused renal tubule damage, induced apoptosis, and promoted neutrophil influx. Urografin also increased kidney protein levels of proinflammatory cytokines, and kidney mRNA levels of proinflammatory cytokines, kidney injury biomarkers, and enzymes responsible for reactive oxygen and nitrogen species. PACAP38 significantly reduced these Urografin-induced changes in eNOS(-/-) mice. This study shows that both Urografin and iohexol are toxic to HK-2 cells, but Urografin is more toxic than iohexol. Urografin causes acute kidney injury in eNOS(-/-) mice. PACAP38 protects HK-2 cells and mouse kidneys from contrast media and is a potential therapeutic agent for contrast-induced nephropathy.

Kidney injury biomarkers in hypertensive, diabetic, and nephropathy rat models treated with contrast media.

Contrast-induced nephropathy (CIN) refers to a decline in renal function following exposure to iodinated contrast media (CM). The present study was initiated to explore the role of known human risk factors (spontaneous hypertension, diabetes, protein-losing nephropathy) on CIN development in rodent models and to determine the effect of CM administration on kidney injury biomarkers in the face of preexisting kidney injury. Spontaneously hypertensive rats (hypertension), streptozotocin-treated Sprague Dawley rats (diabetes), and Dahl salt-sensitive rats (protein-losing nephropathy) were given single intravenous injections of the nonionic, low osmolar contrast medium, iohexol. Blood urea nitrogen (BUN), serum creatinine (sCr), and urinary biomarkers; albumin, lipocalin 2 (Lcn-2), osteopontin (Opn), kidney injury molecule 1 (Kim-1), renal papillary antigen 1 (Rpa-1), α-glutathione S-transferase (α-Gst), µ-glutathione S-transferase (µ-Gst), and beta-2 microglobulin (ß2m) were measured in disease models and appropriate controls to determine the response of these biomarkers to CM administration. Each disease model produced elevated biomarkers of kidney injury without CM. Preexisting histopathology was exacerbated by CM but little or no significant increases in biomarkers were observed. When 1.5-fold or greater sCr increases from pre-CM were used to define true positives, receiver-operating characteristic curve analysis of biomarker performance showed sCr was the best predictor of CIN across disease models. ß2m, Lcn-2, and BUN were the best predictors of histopathology defined kidney injury.