Long-Term Sodium Deficiency Reduces Sodium Excretion but Impairs Renal Function and Increases Stone Formation in Hyperoxaluric Calcium Oxalate Rats.

Excessive sodium intake is associated with nephrolithiasis, but the impact of sodium-deficient (SD) diets is unknown. Hence, we investigated the effects of short- and long-term SD diets on the expression of renal aquaporins and sodium transporters, and thus calcium oxalate (CaOx) crystal formation in hyperoxaluria rats. In a short-term sodium balance study, six male rats received drinking water and six received 0.75% ethylene glycol (EG) to induce hyperoxaluria. After a 30-day period of feeding on normal chow, both groups were treated with a normal-sodium diet for 5 days, followed by a sodium-free diet for the next 5 days. In a long-term SD study (42 days), four groups, induced with EG or not, were treated with normal-sodium water and sodium-free drinking water, alternately. Short-term sodium restriction in EG rats reversed the daily positive sodium balance, but progressively caused a negative cumulative water balance. In the long-term study, the abundant levels of of Na/H exchanger, thiazide-sensitive Na-Cl cotransporter, Na-K-ATPase, and aquaporins-1 from SD + EG rats were markedly reduced, corresponding to a decrease in Uosm, as compared to SD rats. Increased urine calcium, AP(CaOx)index, and renal CaOx deposition were also noted in SD + EG rats. Although the SD treatment reduced sodium excretion, it also increased urinary calcium and impaired renal function, ultimately causing the formation of more CaOx crystals.

Increased risk of chronic kidney disease in uric acid stone formers with high neutrophil-to-lymphocyte ratio.

Urolithiasis is associated with an increased risk of chronic kidney disease (CKD), irrespective of stone compositions. Chronic inflammation is an important factor for CKD progression. Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a reliable biomarker of inflammation, yet its use in predicting renal deterioration in patients with urolithiasis remains limited. We aimed to explore whether the combination of stone composition and NLR could be useful as a predictor for CKD risk. A total of 336 stone formers with at least one stone submission for analysis were enrolled in the retrospective study. Stones were classified into uric acid and calcium groups. Renal functions were assessed at least one month after stone treatment. Uric acid stone formers had significantly lower estimated glomerular filtration rate (eGFR) compared with calcium stone formers (p < 0.001). NLR was significantly higher in uric acid stone formers (p = 0.005), and a significantly negative correlation (p < 0.001) between NLR and eGFR had been observed only in uric acid stone group. Univariate and multivariate logistic regression analyses showed that higher proportion of uric acid stone composition and higher NLR were both significantly associated with CKD risks. A nomogram integrating independent predictors was generated for CKD prediction, yielding an AUC of 0.811 (0.764-0.858). In conclusion, our study demonstrated that stone formers with higher proportion of uric acid composition and higher NLR levels were associated with higher CKD risk.

The Mayo adhesive probability score predicts postoperative fever and intraoperative hemorrhage in mini-percutaneous nephrolithotomy.

PURPOSE: Contemporary predictive tools for miniaturized percutaneous nephrolithotomy (mPCNL) mainly focus on stone clearance but not perioperative complications, especially infection and hemorrhage. This study aimed to evaluate whether the Mayo adhesive probability (MAP) score, an index of the perinephric fat characteristics, can predict postoperative fever and intraoperative hemorrhage in mPCNL. METHODS: This is a retrospective study recruiting 159 mPCNL patients from July 2018 to January 2022. MAP scores were recorded using preoperative computed tomography. Postoperative complications included postoperative fever and intraoperative bleeding, defined as hemoglobin drop. RESULTS: Over half patients had the MAP score ≧ 3. Men, elderly, chronic kidney disease, and diabetes were associated with a higher MAP score. The patients with a higher MAP score were more likely to have postoperative fever after mPCNL. On multivariate analysis, preoperative positive urine culture (OR 2.68) and a higher MAP score (OR 2.28) were both significantly associated with postoperative fever. ROC curves analysis of the combination of these two factors on predicting postoperative fever showed AUC values were 0.731 (0.652-0.810). Moreover, a higher MAP score (OR 2.30) and longer operative time (OR 2.16) were significantly associated with higher hemoglobin drop on multivariate analysis. CONCLUSION: A high MAP score was associated with postoperative fever and intraoperative hemorrhage in patients undergoing mPCNL. The MAP score can be a novel and easy predictive tool to help endourologists improve the awareness of mPCNL safety.

Nephrolithiasis is associated with the severity of coronary artery calcification, but not with coronary artery stenosis.

PURPOSE: Emerging data have indicated that nephrolithiasis is possibly associated with subclinical coronary artery disease (CAD). Considering that a significant proportion of obstructive CAD in non-elderly individuals occurs in those without detectable calcium score (CACS), this study aimed to investigate whether nephrolithiasis is still associated with CAD as assessed by coronary computed tomography (CT)-derived luminal stenosis [using Gensini score (GS)]. METHODS: A total of 1170 asymptomatic adults without known CAD who underwent health examinations were recruited. Nephrolithiasis was assessed using abdominal ultrasonography (US). Individuals with a self-reported stone history, but no evidence of nephrolithiasis were excluded. The CACS and GS were measured using 256-slice coronary CT. RESULTS: Nearly half of these patients had a CACS > 0 (48.1%), and a higher prevalence of nephrolithiasis was observed than in those who had zero CACS (13.1% vs. 9.7%). However, no significant intergroup difference in GS was detected. A greater proportion of stone formers than non-stone formers had a higher risk category, whereas no significant difference was noted in Gensini category. Multiple linear regression analyses showed that the CACS independently predicted the presence of nephrolithiasis after adjustment. Importantly, we found that stone formers had a nearly threefold higher risk than non-stone formers of developing severe coronary calcification (CAC > 400). CONCLUSIONS: Nephrolithiasis was significantly associated with coronary artery calcification presence and severity, but not coronary luminal stenosis in patients without known CAD. Accordingly, the relationship between stone disease and CAD remains controversial, and additional studies are imperative to validate these findings.

Increased renal uptake and urine excretion of oxidized LDL is possibly associated with formation of large calcium oxalate nephrolithiasis: a preliminary study.

PURPOSE: Growing evidence have suggested an association between nephrolithiasis and cardiovascular disease (CVD) with unclear mechanism. Oxidized low-density lipoproteins (oxLDL) induces atherosclerosis and was found to be the possible link between these two diseases. Our study aimed to examine the serum, urine and kidney expression of oxLDL in relation to large calcium oxalate (CaOx) renal stone disease. METHODS: A total of 67 large CaOx dominant renal stone patients and 31 stone-free controls were enrolled in the prospective case-control study. All participants were without known CVD history. Serum, urine, and kidney biopsy were collected before and during percutaneous nephrolithotomy, respectively. Enzyme-linked immunosorbent assays were used to assess serum and urine oxLDL, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and high-sensitivity C-reactive protein (hsCRP). RESULTS: There was no significantly difference in circulating oxLDL, but serum hsCRP was significantly near two-fold higher in nephrolithiasis patients. Serum hsCRP was also correlated with stone maximal length. Urine oxLDL was significantly higher in the nephrolithiasis group and correlated with serum hsCRP and stone maximal length. Increased oxLDL uptake in kidney was found in nephrolithiasis patients, whereas no significantly renal expression of oxLDL was observed in controls. CONCLUSIONS: The renal uptake of oxLDL with increased oxLDL excretion from large CaOx renal stone formers, independent of increased circulating oxLDL, is a novel pathological finding in kidney stone disease and brings attention to the possible involvement of renal steatosis in the process of urolithiasis formation.

Use of Urine N-Terminal Prohormone of Brain-Natriuretic Peptide (NT-proBNP) as a Non-Invasive Indicator for Renal Function Recovery after Surgical Relief of Hydronephrosis.

Cardiorenal syndrome is rarely discussed in patients with obstructive uropathy. On the other hand, there is currently no accurate and convenient clinical biomarker to predict the recovery of renal function after the resolution of ureteral obstruction. The purpose of this study is to explore the association between hydronephrosis and cardiorenal syndrome by measuring the change of the N-terminal prohormone of brain-natriuretic peptide (NT-proBNP), which is a biomarker typically used for cardiac failure, in patients receiving surgery to relieve obstructive uropathy. A total of 212 patients admitted for ureteroscopic (URS) procedures to relieve hydronephrosis were enrolled in this study. The severity of hydronephrosis as well as plasma and urine NT-proBNP levels were obtained before and after surgery. The results showed a significant correlation between urine NT-proBNP levels and renal function recovery following the resolution of hydronephrosis (OR 3.24, 95% CI 1.09−9.70, p = 0.035). Urine NT-proBNP could even predict the recovery of renal function with an area under the ROC = 0.775 (0.65−0.88, p < 0.001). In conclusion, urine NT-proBNP could be a useful early marker of renal function recovery after URS surgery, identifying patients whose renal and heart functions were compromised by the obstruction.

Risks of Carotid Artery Stenosis and Atherosclerotic Cardiovascular Disease in Patients with Calcium Kidney Stone: Assessment of Systemic Inflammatory Biomarkers.

(1) Background: To assess the clinical significance of preoperative inflammatory biomarkers combined with atherosclerotic cardiovascular disease (ASCVD) risk score to evaluate carotid artery stenosis in patients with calcium kidney stones; (2) Methods: We conducted a prospective observational case-control study, enrolling 74 patients with calcium kidney stones and 66 age- and sex-matched healthy controls. We calculated the inflammatory biomarkers including the neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and systemic inflammation response index (SIRI). An ultrasound of the carotid arteries was performed on all participants to identify the severity of the stenosis; (3) Results: All inflammatory biomarkers and the severity of carotid artery stenosis were higher in the calcium kidney stone group than in controls. After stratification of ASCVD, inflammatory biomarkers and carotid artery stenosis severity were still significantly higher in the calcium kidney stone group. Multivariate analyses showed that calcium kidney stones significantly increased the risk of ASCVD and carotid artery stenosis. In multivariate linear logistic regression analyses, calcium kidney stone and ASCVD score had a significant association with carotid artery occlusion, but SIRI did not; (4) Conclusions: Calcium kidney stone is associated with higher levels of inflammatory biomarkers and carotid artery stenosis. Calcium kidney stone is associated with higher levels of inflammatory biomarkers and carotid artery stenosis.

Ureterorenoscopic (URS) Lithotripsy and Balloon Dilation Cause Acute Kidney Injury and Distal Renal Tubule Damage: A Prospective Study.

Ureterorenoscopy (URS) is believed to be a safe and effective procedure for treating ureteral stones or ureteral strictures. Rapidly increasing intrarenal pressure during URS may have a negative impact on the kidney, but its effect on renal function is not well known. The aim of this study was to evaluate whether URS balloon dilation or lithotripsy could cause acute kidney injury (AKI), which was evaluated using urine neutrophil gelatinase-associated lipocalin (NGAL), and renal tubular damage, which was evaluated using urine α-glutathione S-transferase (GST) and πGST. This prospective study included 207 patients with a mean age of 53.8 years between September 2012 and June 2013. Four groups were included: the ureteral stricture group (group 1), the ureteral stone group (group 2), and two control groups. URS increased urine NGAL (uNGAL) levels on days 1 and 14 in both groups, and only elevated uGST levels were noted on day 14 after URS lithotripsy (URS). On day 14, the difference between low-grade and high-grade hydronephrosis was significant in group 1 (p < 0.001) compared to that in group 2 (p = 0.150). Multivariate logistic regression analysis revealed that age, baseline estimated glomerular filtration rate (eGFR), and stone size > 1.0 cm were associated with the complete recovery of hydronephrosis after URS on day 14. Patients with ureteral stones with preserved renal function had more AKI than those with impaired renal function. However, there was no significant difference in URS-related AKI between the ≤1 cm and >1 cm subgroups. In addition, urine αGST and πGST levels were both significantly higher in the stone > 1 cm subgroup than in the ≤1 cm subgroup. In conclusion, URS laser lithotripsy and balloon dilatation resulted in AKI and renal tubular damage on day 14, although post-URS double-J (DBJ) stenting was performed in every patient.

Atorvastatin Decreases Renal Calcium Oxalate Stone Deposits by Enhancing Renal Osteopontin Expression in Hyperoxaluric Stone-Forming Rats Fed a High-Fat Diet.

Calcium oxalate (CaOx) is the major constituent of kidney stones. Growing evidence shows a close connection between hyperlipidemia, cardiovascular disease (CVD), and the formation of kidney stones. Owing to their antioxidant properties, statins control hyperlipidemia and may ameliorate CaOx stone formation. The present study was designed to investigate the suppressive effects of statins on CaOx urolithiasis and their potential mechanism. We used rats fed a high-fat diet (HFD) to achieve hyperlipidemia (HL) and hydroxyproline (HP) water to establish a hyperoxaluric CaOx nephrolithiasis model; the animals were administered statins (A) for 28 days. The rats were divided into eight groups treated or not with A, i.e., Control, HP, HL, HL + HP. HL aggravated urinary calcium crystallization compared to the control. Due to increased expression of renal osteopontin (OPN), a key anti-lithic protein, and reduced free radical production, the calcium crystals in the urinary bladder increased as renal calcium deposition decreased. The levels of the ion activity product of CaOx (AP(CaOx)) decreased after statins administration, and AP(Calcium phosphate) (CaP) increased, which suggested the dominant calcium crystal composition changed from CaOx to CaP after statin administration. In conclusion, atorvastatin decreases renal CaOx stone deposits by restoring OPN expression in hyperoxaluric rats fed a HFD.

Preoperative Urine Analysis is An Effective Tool to Predict Fever After Miniaturized Percutaneous Nephrolithotomy on Large Renal Stones.

PURPOSE: To investigate the preoperative and intraoperative potential risk factors associated with miniaturized percutaneous nephrolithotomy (mPCNL) fever in the treatment of patients with large renal stones. MATERIALS AND METHODS: All patients with renal stones larger than 2.5 cm, who had undergone mPCNL, were included in the period between April 2018 and September 2019. Logistic regression analyses were performed to identify clinical variables associated with post-operative fever (>38°C). RESULTS: A total of 53 patients were enrolled for whom the median maximal stone length was 3.08 cm. 24 (45%) patients had a fever after mPCNL. Significantly more patients with urine WBC ≥ 27(/HPF) had a fever after surgery (p = 0.004). No significant between-group differences in urine cultures were found for the fever and non-fever groups (p = 0.094). Stepwise and multivariable logistic regression analyses all revealed that urine WBC ≥ 27(/HPF) is the only risk factor for developing post-mPCNL fever. Based on the highest body temperature, all of the patients were assigned into no fever, mild fever (37.5 ≤ Temp < 38.0), and fever groups, and an ordinal logistic regression analysis still supported the premise that the result of urine analysis is strongly associated with post-mPCNL fever. CONCLUSION: Large renal stones are challenging to treat and associated with severe complications. Approximately 45% of large renal stone patients treated via mPCNL developed a fever. Urine WBC can easily and directly predict the risk of fever.

Crosstalk between Renal and Vascular Calcium Signaling: The Link between Nephrolithiasis and Vascular Calcification.

Calcium (Ca2+) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca2+ homeostasis is strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca2+ regulation. CaSR is important for renal Ca2+, as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca2+ sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca2+ homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.

Statins significantly alter urinary stone-related urine biochemistry in calcium kidney stone patients with dyslipidemia.

OBJECTIVE: To investigate whether the use of statins would alter 24-h urine biochemistry in male patients with calcium kidney stones. METHODS: We prospectively recruited 78 male patients with calcium kidney stones between May 2017 and December 2017, and 30 male controls with matching sex and age, but without kidney stones. All patients were classified into higher- and lower-risk groups of atherosclerotic cardiovascular disease according to the American College of Cardiology/American Heart Association guidelines. Atorvastatin 20 mg per day was prescribed for 12 weeks to the higher risk patients. For kidney stone group, 24-h urine collections were carried out before and after statin therapy. RESULTS: A total of 78 patients and 30 controls were included. Higher-risk patients had significantly higher urine uric acid and calcium levels than lower-risk patients. After atorvastatin treatment for 12 weeks, urine citrate significantly increased (P < 0.001) accompanied with increased urine pH (P < 0.001), whereas urine uric acid significantly decreased after treatment. Although urine oxalate significantly increased after treatment (P = 0.037), we did not find any significant difference in urine calcium, ion activity product of calcium oxalate and ion activity product of calcium phosphate. CONCLUSION: These findings suggest that atorvastatin administration might increase urinary citrate and decrease urinary uric acid in patients with calcium kidney stones and dyslipidemia.

Calcium Kidney Stones are Associated with Increased Risk of Carotid Atherosclerosis: The Link between Urinary Stone Risks, Carotid Intima-Media Thickness, and Oxidative Stress Markers.

Previous studies have suggested that kidney stone formers are associated with a higher risk of cardiovascular events. To our knowledge, there have been no previous examinations of the relationship between carotid intima-media thickness (IMT) and urinary stone risk factors. This study was aimed toward an investigation of the association between dyslipidemia, IMT, and 24-hour urinalysis in patients with calcium oxalate (CaOx) or calcium phosphate (CaP) stones. We prospectively enrolled 114 patients with kidney stones and 33 controls between January 2016 and August 2016. All patients were divided into four groups, according to the stone compositions-CaOx ≥ 50% group, CaP group, struvite group, and uric acid stones group. Carotid IMT and the carotid score (CS) were evaluated using extracranial carotid artery doppler ultrasonography. The results of a multivariate analysis indicated that a higher serum total cholesterol (TC) and low-density lipoprotein (LDL) were all associated with lower urinary citrate and higher CS in both the CaOx ≥ 50% and CaP groups. Higher serum TC and LDL were also associated with increased serum 8-OHdG levels in both groups. The levels of carotid IMT and CS in the CaOx ≥ 50% and CaP groups were all significantly higher than in the controls. These findings suggest a strong link between dyslipidemia, carotid atherosclerosis, and calcium kidney stone disease.

Biomarkers and echocardiography for evaluating the improvement of the ventricular diastolic function after surgical relief of hydronephrosis.

The pathophysiology of cardio-renal syndrome (CRS) is complex. Hydronephrosis caused by urolithiasis may cause cytokine release and lead to cardiac dysfunction. The aim of this study was to evaluate cardiac function changes observed in patients who received double J placement using feasible biomarkers and echocardiography. This was a prospective, single-center study. Eighty-seven patients who presented with acute unilateral hydronephrosis and received ureteroscope stone manipulation were enrolled. Echocardiography and cytokines were measured on the day of the operation and 24 hours after the procedure. Changes before and after surgery were assessed by the paired t-test and Wilcoxon test. Correlation analyses between echocardiographic diastolic indices and cytokine levels were performed using Pearson's correlation coefficients. Patients with hydronephrosis showed a higher left atrium volume index (LAVI), decreased E', and increased E/ E' ratio, which indicated diastolic dysfunction. Patients with hydronephrosis also exhibited decreased global strain rates during isovolumetric relaxation (SRIVR) and E/ SRIVR, which confirmed the diastolic dysfunction. Significant reductions in LAVI, increases in SRIVR and decreases in E/ SRIVR were observed after the operation. Biomarkers, such as TGF-ß and serum NT-proBNP, were significantly decreased after surgery. In addition, a significant correlation was observed between the post-surgical decrease in TGF-ß1 and increase in SRIVR. Unilateral hydronephrosis causes cardiac diastolic dysfunction, and relieving hydronephrosis could improve diastolic function. Improvements in cardiac dysfunction can be evaluated by echocardiography and measuring cytokine levels. The results of this study will inform efforts to improve the early diagnosis of CRS and prevent further deterioration of cardiac function when treating patients with hydronephrosis.

High Sodium-Induced Oxidative Stress and Poor Anticrystallization Defense Aggravate Calcium Oxalate Crystal Formation in Rat Hyperoxaluric Kidneys.

Enhanced sodium excretion is associated with intrarenal oxidative stress. The present study evaluated whether oxidative stress caused by high sodium (HS) may be involved in calcium oxalate crystal formation. Male rats were fed a sodium-depleted diet. Normal-sodium and HS diets were achieved by providing drinking water containing 0.3% and 3% NaCl, respectively. Rats were fed a sodium-depleted diet with 5% hydroxyl-L-proline (HP) for 7 and 42 days to induce hyperoxaluria and/or calcium oxalate deposition. Compared to normal sodium, HS slightly increased calcium excretion despite diuresis; however, the result did not reach statistical significance. HS did not affect the hyperoxaluria, hypocalciuria or supersaturation caused by HP; however, it increased calcium oxalate crystal deposition soon after 7 days of co-treatment. Massive calcium oxalate formation and calcium crystal excretion in HS+HP rats were seen after 42 days of treatment. HP-mediated hypocitraturia was further exacerbated by HS. Moreover, HS aggravated HP-induced renal injury and tubular damage via increased apoptosis and oxidative stress. Increased urinary malondialdehyde excretion, in situ superoxide production, NAD(P)H oxidase and xanthine oxidase expression and activity, and decreased antioxidant enzyme expression or activity in the HS+HP kidney indicated exaggerated oxidative stress. Interestingly, this redox imbalance was associated with reduced renal osteopontin and Tamm-Horsfall protein expression (via increased excretion) and sodium-dependent dicarboxylate cotransporter NaDC-1 upregulation. Collectively, our results demonstrate that a HS diet induces massive crystal formation in the hyperoxaluric kidney; this is not due to increased urinary calcium excretion but is related to oxidative injury and loss of anticrystallization defense.

Blockade of the N-Methyl-D-Aspartate Glutamate Receptor Ameliorates Lipopolysaccharide-Induced Renal Insufficiency.

N-methyl-D-aspartate (NMDA) receptor activation in rat kidney reduces renal perfusion and ultrafiltration. Hypoperfusion-induced ischemia is the most frequent cause of functional insufficiency in the endotoxemic kidney. Here, we used non-hypotensive rat model of lipopolysaccharide-induced endotoxemia to examine whether NMDA receptor hyperfunction contributes to acute kidney injury. Lipopolysaccharide-induced renal damage via increased enzymuria and hemodynamic impairments were ameliorated by co-treatment with the NMDA receptor blocker, MK-801. The NMDA receptor NR1 subunit in the rat kidney mainly co-localized with serine racemase, an enzyme responsible for synthesizing the NMDA receptor co-agonist, D-serine. The NMDA receptor hyperfunction in lipopolysaccharide-treated kidneys was demonstrated by NR1 and serine racemase upregulation, particularly in renal tubules, and by increased D-serine levels. Lipopolysaccharide also induced cell damage in cultured tubular cell lines and primary rat proximal tubular cells. This damage was mitigated by MK-801 and by small interfering RNA targeting NR1. Lipopolysaccharide increased cytokine release in tubular cell lines via toll-like receptor 4. The release of interleukin-1ß from these cells are the most abundant. An interleukin-1 receptor antagonist not only attenuated cell death but also abolished lipopolysaccharide-induced NR1 and serine racemase upregulation and increases in D-serine secretion, suggesting that interleukin-1ß-mediated NMDA receptor hyperfunction participates in lipopolysaccharide-induced tubular damage. The results of this study indicate NMDA receptor hyperfunction via cytokine effect participates in lipopolysaccharide-induced renal insufficiency. Blockade of NMDA receptors may represent a promising therapeutic strategy for the treatment of sepsis-associated renal failure.

H2O2 generated by NADPH oxidase 4 contributes to transient receptor potential vanilloid 1 channel-mediated mechanosensation in the rat kidney.

The presence of NADPH oxidase (Nox) in the kidney, especially Nox4, results in H2O2 production, which regulates Na(+) excretion and urine formation. Redox-sensitive transient receptor potential vanilloid 1 channels (TRPV1s) are distributed in mechanosensory fibers of the renal pelvis and monitor changes in intrapelvic pressure (IPP) during urine formation. The present study tested whether H2O2 derived from Nox4 affects TRPV1 function in renal sensory responses. Perfusion of H2O2 into the renal pelvis dose dependently increased afferent renal nerve activity and substance P (SP) release. These responses were attenuated by cotreatment with catalase or TRPV1 blockers. In single unit recordings, H2O2 activated afferent renal nerve activity in response to rising IPP but not high salt. Western blots revealed that Nox2 (gp91(phox)) and Nox4 are both present in the rat kidney, but Nox4 is abundant in the renal pelvis and originates from dorsal root ganglia. This distribution was associated with expression of the Nox4 regulators p22(phox) and polymerase δ-interacting protein 2. Coimmunoprecipitation experiments showed that IPP increases polymerase δ-interacting protein 2 association with Nox4 or p22(phox) in the renal pelvis. Interestingly, immunofluorescence labeling demonstrated that Nox4 colocalizes with TRPV1 in sensory fibers of the renal pelvis, indicating that H2O2 generated from Nox4 may affect TRPV1 activity. Stepwise increases in IPP and saline loading resulted in H2O2 and SP release, sensory activation, diuresis, and natriuresis. These effects, however, were remarkably attenuated by Nox inhibition. Overall, these results suggest that Nox4-positive fibers liberate H2O2 after mechanostimulation, thereby contributing to a renal sensory nerve-mediated diuretic/natriuretic response.

Perfusion index derived from a pulse oximeter can detect changes in peripheral microcirculation during uretero-renal-scopy stone manipulation (URS-SM).

BACKGROUND: The objective of this study was to test the effect of removal of a ureteral obstruction (renal calculus) from anesthetized patients on the perfusion index (PI), as measured by a pulse oximeter, and on the estimated glomerular filtration rate (eGFR). PATIENTS AND METHODS: This prospective study enrolled 113 patients with unilateral ureteral obstructions (kidney stones) who were scheduled for ureteroscopy (URS) laser lithotripsy. One urologist graded patient hydronephrosis before surgery. A pulse oximeter was affixed to each patient's index finger ipsilateral to the intravenous catheter, and a non-invasive blood pressure cuff was placed on the contralateral side. Ipsilateral double J stents and Foley catheters were inserted and left indwelling for 24 h. PI and mean arterial pressure (MAP) were determined at baseline, 5 min after anesthesia, and 10 min after surgery; eGFR was determined at admission, 1 day after surgery, and 14 days after surgery. RESULTS: Patients with different grades of hydronephrosis had similar age, eGFR, PI, mean arterial pressure (MAP), and heart rate (HR). PI increased significantly in each hydronephrosis group after ureteral stone disintegration. None of the groups had significant post-URS changes in eGFR, although eGFR increased in the grade I hydronephrosis group after 14 days. The percent change of PI correlates significantly with the percent change of MAP, but not with that of eGFR. CONCLUSION: Our results demonstrate that release of a ureteral obstruction leads to a concurrent increase of PI during anesthesia. Measurement of PI may be a valuable tool to monitor the successful release of ureteral obstructions and changes of microcirculation during surgery. There were also increases in eGFR after 14 days, but not immediately after surgery.

Hypoxic preconditioning protects rat hearts against ischemia-reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway.

Hypoxic preconditioning (HPC) protects rat hearts against ischemia-reperfusion (IR) injury. However, the role of transient receptor potential vanilloid 1 (TRPV1) in HPC-mediated cardioprotection remains unknown. TRPV1 is activated by endovanilloid 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which is synthesized by arachidonate 12-lipoxygenase (ALOX12). Therefore, we examined whether HPC protects the myocardium against IR via the ALOX12/TRPV1 pathway. Compared to hearts of rats kept in room air, the hearts of rats kept in air with 10 % oxygen for 4 weeks had better post-ischemic recovery and less tissue damage when subjected to 30-min global ischemia and 4-h reflow in a Langendorff apparatus. Capsazepine, a specific TRPV1 blocker, administered 5 min before reperfusion markedly attenuated the effects of HPC, confirming that TRPV1 is a downstream effector in HPC-mediated cardioprotection. HPC resulted in the upregulation of ALOX12 and myocardial 12(S)-HETE, and prevented IR-induced 12(S)-HETE reduction. In addition, sarcolemmal ALOX12 expression in HPC hearts mainly co-localized with TRPV1 expression. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein abrogated the effects of HPC, baicalein also decreased 12(S)-HETE expression. Mimicking HPC by given 12(S)-HETE or capsaicin to baicalien-treated hearts enhanced cardiac recovery during reperfusion. The cardiac protein kinase C (PKC) isoforms α, δ, ε, and ζ were preferentially expressed in the sarcolemmal membrane of HPC-treated hearts, indicating their high intrinsic activation state. Capsazepine or co-treatment with baicalein attenuated translocation of PKCα, PKCδ and PKCε, but not that of PKCζ. We conclude that HPC reduces heart susceptibly to IR via ALOX12/TRPV1/PKC pathway, as shown by increased 12(S)-HETE expression in HPC hearts.