Urinary MicroRNA Biomarkers of Nephrotoxicity in Macaca fascicularis.

Drug-induced kidney injury (DIKI) refers to kidney damage resulting from the administration of medications. The aim of this project was to identify reliable urinary microRNA (miRNAs) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. This study quantified a panel of six miRNAs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) across multiple time points using urinary samples from a previous investigation evaluating effects of a nephrotoxicant in cynomolgus monkeys. Exosome-associated miRNA exhibited distinctive trends when compared to miRNAs quantified in whole urine, which may reflect a different urinary excretion mechanism of miRNAs than those released passively into the urine. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials. Also, these findings can potentially be translated into other non-clinical species or human for the detection of DIKI.

Updates of perioperative multidisciplinary treatment for surgically resectable esophageal cancer.

Esophageal cancer has one of the poorest prognoses among all cancer types, due to the propensity for an early spread through the lymphatics and the difficulty to perform surgical treatment. To improve the prognosis, the management of esophageal cancer has been developed through the conduct of several clinical trials worldwide. In western societies, neoadjuvant chemoradiotherapy has been established as the standard treatment approach, as indicated by the results of the CROSS trial. Recently, the Japanese JCOG1109 trial demonstrated the significant improvement of survival by neoadjuvant triplet chemotherapy. As an adjuvant treatment, an immune checkpoint inhibitor has shown promising results in the CheckMate-577 trial. Including adjuvant S-1 mono therapy as another option, a randomised control phase III study will determine the ideal treatment for surgically resectable esophageal cancer. Furthermore, the efficacy and safety of neoadjuvant cisplatin +5-fluorouracil or DCF plus nivolumab are examined in the JCOG1804E (FRONTiER) study. In addition to definitive chemoradiation therapy, the SANO trial is examining the safety and efficacy of active surveillance after neoadjuvant chemoradiotherapy, which might give us the choice to adopt organ preservation approach. The development of treatment has progressed dramatically with the advent of immunotherapy. Considering the biomarkers to predict the treatment response and prognosis, individualised multidisciplinary treatment strategies should be established for esophageal cancer patients.

Evaluation of surgical complexity by automated surgical process recognition in robotic distal gastrectomy using artificial intelligence.

BACKGROUND: Although radical gastrectomy with lymph node dissection is the standard treatment for gastric cancer, the complication rate remains high. Thus, estimation of surgical complexity is required for safety. We aim to investigate the association between the surgical process and complexity, such as a risk of complications in robotic distal gastrectomy (RDG), to establish an artificial intelligence (AI)-based automated surgical phase recognition by analyzing robotic surgical videos, and to investigate the predictability of surgical complexity by AI. METHOD: This study assessed clinical data and robotic surgical videos for 56 patients who underwent RDG for gastric cancer. We investigated (1) the relationship between surgical complexity and perioperative factors (patient characteristics, surgical process); (2) AI training for automated phase recognition and model performance was assessed by comparing predictions to the surgeon-annotated reference; (3) AI model predictability for surgical complexity was calculated by the area under the curve. RESULT: Surgical complexity score comprised extended total surgical duration, bleeding, and complications and was strongly associated with the intraoperative surgical process, especially in the beginning phases (area under the curve 0.913). We established an AI model that can recognize surgical phases from video with 87% accuracy; AI can determine intraoperative surgical complexity by calculating the duration of beginning phases from phases 1-3 (area under the curve 0.859). CONCLUSION: Surgical complexity, as a surrogate of short-term outcomes, can be predicted by the surgical process, especially in the extended duration of beginning phases. Surgical complexity can also be evaluated with automation using our artificial intelligence-based model.

Clinical Significance of Endoscopic Response Evaluation to Predict the Distribution of Residual Tumor after Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

PURPOSE: To appropriately adopt the organ preservation approach, including subsequent chemoradiotherapy (CRT) in patients who respond to neoadjuvant chemotherapy (NAC), the distribution of residual disease, including pathological lymph nodes (LNs) and recurrence site, needs to be recognized preoperatively. This study was designed to evaluate whether endoscopic response evaluation can predict residual tumor distribution. METHODS: Patients with esophageal squamous cell carcinoma who underwent transthoracic esophagectomy (TTE) were retrospectively reviewed. Endoscopic responder (ER) to NAC was defined according to primary tumor endoscopic findings. Recurrence-free survival (RFS), overall survival (OS), and residual tumor patterns were compared between groups. RESULTS: Of 193 patients, 40 (20%) were classified as ER. ERs showed significantly better RFS and OS. The pN location was found within the primary tumor and cN field in 88% of ERs, which was significantly higher than non-ERs at 63% (p = 0.004). Furthermore, the postoperative recurrence incidence in the distant organ was significantly lower in the ERs than the non-ERs (8%, 32%, respectively, p = 0.002). Residual disease, including postoperative initial recurrence, existed within the same field as the primary tumor and cN in 88% of ERs, significantly higher than 42% in the non-ERs (p < 0.001). CONCLUSIONS: Endoscopic response evaluation can preoperatively predict distribution of residual tumors after NAC, which could help radiation field selection in subsequent definitive CRT when patients prefer to omit TTE. Along with improvements in NAC response rate, this could facilitate organ preservation in patients who respond to NAC.

IL-17A activated by Toll-like receptor 9 contributes to the development of septic acute kidney injury.

Toll-like receptor 9 (TLR9), which is activated by endogenously released mtDNA during sepsis, contributes to the development of polymicrobial septic acute kidney injury (AKI). However, downstream factors of TLR9 to AKI remain unknown. We hypothesized that IL-17A activated by TLR9 may play a critical role in septic AKI development. To determine the effects of TLR9 on IL-17A production in septic AKI, we used a cecal ligation and puncture (CLP) model in Tlr9 knockout (Tlr9KO) mice and wild-type (WT) littermates. We also investigated the pathway from TLR9 activation in dendritic cells (DCs) to IL-17A production by γδT cells in vitro. To elucidate the effects of IL-17A on septic AKI, Il-17a knockout (Il-17aKO) mice and WT littermates were subjected to CLP. We further investigated the relationship between the TLR9-IL-17A axis and septic AKI by intravenously administering recombinant IL-17A or vehicle into Tlr9KO mice and assessing kidney function. IL-17A levels in both plasma and the peritoneal cavity and mRNA levels of IL-23 in the spleen were significantly higher in WT mice after CLP than in Tlr9KO mice. Bone marrow-derived DCs activated by TLR9 induced IL-23 and consequently promoted IL-17A production in γδT cells in vitro. Knockout of Il-17a improved survival, functional and morphological aspects of AKI, and splenic apoptosis after CLP. Exogenous IL-17A administration aggravated CLP-induced AKI attenuated by knockout of Tlr9. TLR9 in DCs mediated IL-17A production in γδT cells during sepsis and contributed to the development of septic AKI.

Monoclonal immunoglobulin G1 κ-type atypical antiglomerular basement membrane disease accompanied by necrotizing glomerulonephritis
.

INTRODUCTION: Patients without detectable serum antiglomerular basement membrane (GBM) antibodies but with GBM staining for immunoglobulins (Ig), absence of a crescentic phenotype, mild renal insufficiency, and absence of pulmonary hemorrhage have atypical anti-GBM diseases. We report the case of a 64-year-old man with slowly progressive glomerulonephritis. CASE HISTORY: A 64-year-old Peruvian man presented with persistent microscopic hematuria, proteinuria of 2.1 g/g creatinine (Cr), serum Cr 1.00 mg/dL, and C-reactive protein 0.80 mg/dL. Renal biopsy revealed necrotizing glomerulonephritis with 39% cellular crescent formation and diffuse segmental endocapillary proliferation. He had linear staining of monoclonal IgG1-κ in the capillary walls but no detectable serum anti-GBM antibodies. Because renal dysfunction was slowly progressing, steroid monotherapy was initiated, and serum Cr level decreased from 1.48 to 1.13 mg/dL. However, serum Cr increased again to 1.35 mg/dL owing to active glomerular damage with crescent formation and endocapillary proliferation, confirmed by the second renal biopsy at 9 months after therapy. Renal function improved after cyclophosphamide therapy. CONCLUSION: We described an atypical variant of anti-GBM disease due to monoclonal IgG1-κ. Unlike usual atypical anti-GBM disease cases, we observed crescent formation in our patient. Further investigations are needed to identify the cause of nondetectable serum anti-GBM antibodies and to describe the causal relationships between clinicopathological features and the pattern of IgG subclass and light chain in atypical anti-GBM disease.

Correction to: Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

In the original publication, an error occurred in Table 4 (B), under Nighttime group. The value of "Nighttime Log U-AGT/Cr" for model 3 (under R = 0.68) was incorrectly published as 0.11. The correct value should read as -0.31.

A case report of thin basement membrane nephropathy accompanied by sporadic glomerulocystic kidney disease.

BACKGROUND: Thin basement membrane nephropathy (TBMN) is a relatively common disease. Patients typically present with isolated hematuria, which has a good renal prognosis. In contrast, glomerulocystic kidney disease (GCKD) is a rare disease, associated with slow progressive renal dysfunction. To our knowledge, co-occurring diagnosis of TBMN with GCKD has not been reported previously. CASE PRESENTATION: A 30-year old woman was admitted to our hospital for evaluation of hematuria and renal insufficiency. Upon examination, her urinary protein level was 40 mg/day and occult blood in her urine was 2+. The patient's urinary dysmorphic red blood cell sediment was 30-49/high power field. In contrast, her serum creatinine levels increased from 0.57 mg/dl to 0.86 mg/dl during the previous 2-years, without special events. She suffered from far-sightedness and astigmatism beginning at birth; She had no family history of renal disease. Renal biopsy demonstrated cystic dilatation of the Bowman's capsule and atrophy of the glomerular tuft. The glomerular basement membrane (GBM) was thin, with an average thickness of 191 nm. Next-generation sequencing was used to evaluate for mutations in COL4A3 and COL4A4, associated with TBMN, and UMOD, MUC1, and SEC61A1, associated with hereditary GCKD. No pathogenic mutations were identified. We thus diagnosed the patient with TBMN coexistent with sporadic GCKD. CONCLUSION: We report the patient diagnosed with TBMN accompanied by sporadic GCKD, based on renal biopsy and genetic testing. Because it is possible that other diseases, such as GCKD, can coexist with TBMN, it is important to consider renal biopsy.

The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia.

BACKGROUND: Febuxostat is tolerable in chronic kidney disease (CKD) patients with hyperuricemia. However, the long-term effect of lowering uric acid with febuxostat on renal function and blood pressure has not been elucidated. METHODS: This was a 2 years retrospective observational study. 86 CKD patients with hyperuricemia who continued with allopurinol (allopurinol group, n = 30), switched from allopurinol to febuxostat (switched group, n = 25), or were newly prescribed febuxostat (febuxostat group, n = 31) were included in this study. Serum uric acid, estimated glomerular filtration rate (eGFR), blood pressure, and urinary protein were analyzed. Moreover, the impact of serum uric acid reduction on renal function and blood pressure was assessed. RESULTS: Serum uric acid in the switched and febuxostat groups was significantly reduced at 6 months (switched group; 8.49 ± 1.32-7.19 ± 1.14 mg/dL, p < 0.0001, febuxostat group; 9.43 ± 1.63-6.31 ± 0.90 mg/dL, p < 0.0001). In the allopurinol group, serum uric acid was increased (6.86 ± 0.87-7.10 ± 0.85 mg/dL, p = 0.0213). eGFR was significantly increased (35.2 ± 12.8-37.3 ± 13.9 mL/min/1.73 m2, p = 0.0232), while mean arterial pressure (93.1 ± 10.8-88.2 ± 9.5 mmHg, p = 0.0039) was significantly decreased at 6 months in the febuxostat group, resulting in the retention of eGFR for 2 years. CONCLUSIONS: The impact of serum uric acid reduction might have beneficial effects on CKD progression and blood pressure. However, a large prospective study is needed to determine the long-term efficacy of febuxostat therapy in CKD patients with hyperuricemia.

Melatonin ameliorates intrarenal renin-angiotensin system in a 5/6 nephrectomy rat model.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production. METHODS: 5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment. RESULTS: Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2'-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (α-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities. CONCLUSION: Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model.

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9.

Toll-like receptor 9 (TLR9) contributes to the development of polymicrobial septic AKI. However, the mechanisms that activate the TLR9 pathway and cause kidney injury during sepsis remain unknown. To determine the role of mitochondrial DNA (mtDNA) in TLR9-associated septic AKI, we established a cecal ligation and puncture (CLP) model of sepsis in wild-type (WT) and Tlr9-knockout (Tlr9KO) mice. We evaluated systemic circulation and peritoneal cavity dynamics and immune response and tubular mitochondrial dysfunction to determine upstream and downstream effects on the TLR9 pathway, respectively. CLP increased mtDNA levels in the plasma and peritoneal cavity of WT and Tlr9KO mice in the early phase, but the increase in the peritoneal cavity was significantly higher in Tlr9KO mice than in WT mice. Concomitantly, leukocyte migration to the peritoneal cavity increased, and plasma cytokine production and splenic apoptosis decreased in Tlr9KO mice compared with WT mice. Furthermore, CLP-generated renal mitochondrial oxidative stress and mitochondrial vacuolization in the proximal tubules in the early phase were reversed in Tlr9KO mice. To elucidate the effects of mtDNA on immune response and kidney injury, we intravenously injected mice with mitochondrial debris (MTD), including substantial amounts of mtDNA. MTD caused an immune response similar to that induced by CLP, including upregulated levels of plasma IL-12, splenic apoptosis, and mitochondrial injury, but this effect was attenuated by Tlr9KO. Moreover, MTD-induced renal mitochondrial injury was abolished by DNase pretreatment. These findings suggest that mtDNA activates TLR9 and contributes to cytokine production, splenic apoptosis, and kidney injury during polymicrobial sepsis.

Severity of Gastric Mucosal Atrophy Is the Major Determinant of Plasma Ghrelin Level in Hemodialysis Patients.

BACKGROUND: Ghrelin, an orexigenic hormone, has multiple favorable functions including protein anabolism enhancement, anti-inflammatory actions, and cardiovascular protection. A low plasma ghrelin level is associated with increased mortality in patients treated with hemodialysis (HD). However, it is unclear whether the plasma ghrelin level in HD patients correlates with the severity of gastric mucosal atrophy and Helicobacter pylori status. METHODS: Seventy-eight maintenance HD patients and 51 non-dialysis patients with chronic kidney disease were evaluated for severity of gastric mucosal atrophy by gastroduodenoscopy and for H. pylori status using an anti-H. pylori-antibody and rapid urease test. Plasma acyl and des-acyl ghrelin levels were measured and their associations with relevant clinical parameters were investigated. RESULTS: Des-acyl ghrelin level in HD patients was significantly higher than that in patients with kidney function preserved. Although acyl and des-acyl ghrelin levels were similar between current H. pylori positive and negative HD patients, both levels decreased significantly with the progress of endoscopic gastric mucosal atrophy in HD patients. Serum pepsinogen (PG) I level and PG I/II ratio decreased significantly according to the severity of atrophy in HD patients and positively significantly correlated with both ghrelin levels. Multiple regression analysis showed significant positive correlations between acyl ghrelin and PG I levels (ß = 0.738, p < 0.001) and significant negative correlations between ghrelin and age, albumin, and creatinine levels. CONCLUSIONS: Gastric atrophy is the major determinant of ghrelin level in HD patients. Management practices, such as H. pylori eradication, before advanced atrophy may be required to prevent the decrease of ghrelin levels and improve the prognosis of HD patients.

Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. METHODS: We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). RESULTS: Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (ß = -0.31, p = 0.044) and U-Alb (ß = -0.25, p = 0.025) only at night. CONCLUSION: Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

Role of intrarenal (pro)renin receptor in ischemic acute kidney injury in rats.

BACKGROUND: (Pro)renin receptor [(P)RR], a trans-membrane receptor for renin and prorenin, is involved in the local activation of renin-angiotensin system (RAS) in the kidney. However, it remains to be determined whether (P)RR plays a role in the development of ischemic acute kidney injury (AKI). METHODS: We examined the abundance of (P)RR, renin/prorenin, angiotensinogen (AGT), AT1 receptor (AT1R), phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and nuclear factor-κB (NF-κB) by Western blots at 6, 24 and 48 h, and at 7 days after 45-min ischemic injury in rats. Intrarenal angiotensin II (Ang II) levels were determined by radioimmunoassay. We then tested whether the beneficial effects of oral loading of saline solution (1.0 % NaCl) for 7 days prior to ischemic injury were associated with changes in RAS components and ERK 1/2 and NF-κB phosphorylation in the kidney. We also examined the effect of AT1R blocker, olmesartan, on ischemia-induced changes of (P)RR downstream such as AGT and phosphorylation of ERK 1/2. RESULTS: Renal ischemia increased the abundance of (P)RR protein at 24 h, and peaked at 48 h. (P)RR was mainly stained in the connecting tubules and collecting ducts in control rats, while ischemia increased its immunointensity in the damaged proximal tubules. Renal ischemia increased phosphorylation of ERK 1/2 and NF-κB proteins as early as at 6 h. There was a significant increase in AGT and Ang II levels at 24 and 48 h. Prior saline loading prevented the increase in serum creatinine at 48 h (5.36 ± 1.26 vs. 3.38 ± 1.74 mg/dL, p < 0.05), and suppressed the increases in renal (P)RR, AGT and Ang II contents. Saline drinking also significantly blocked the ischemia-induced increases in phosphorylation of ERK 1/2 and NF-κB. In contrast, although treatment with olmesartan (10 mg/kg/day) for 14 days suppressed an increase of intrarenal AGT, olmesartan did not alleviate ischemic AKI, along with no change of (P)RR and phosphorylated ERK 1/2. CONCLUSIONS: These findings suggest that increased (P)RR is associated with activation of RAS-independent downstream such as ERK 1/2 and NF-κB phosphorylation in the ischemic kidney.

Disturbed circadian rhythm of the intrarenal renin-angiotensin system: relevant to nocturnal hypertension and renal damage.

BACKGROUND: The intrarenal renin-angiotensin system (RAS) plays an important role in the development of hypertension and renal damage. Disruption of diurnal blood pressure (BP) variation is an additional risk factor for renal damage. However, little is known regarding whether intrarenal RAS circadian rhythm exists or if it influences the disruption of diurnal BP and renal damage. METHODS: We investigated the circadian rhythm of urinary angiotensinogen (U-AGT) that reflects intrarenal RAS activity in 14 individuals without chronic kidney disease (CKD) and 36 CKD patients classified according to circadian BP rhythms. RESULTS: BP values were higher during the daytime than during the nighttime in both individuals without CKD and CKD patients. U-AGT levels were not different between the daytime and nighttime in individuals without CKD, but were significantly higher in the daytime in CKD patients (log U-AGT/creatinine: daytime, 2.39 ± 0.99; nighttime, 2.24 ± 1.06; p = 0.001). Furthermore, in CKD patients showing a riser pattern of circadian BP, U-AGT levels did not decrease during the nighttime compared with those in the daytime (log U-AGT/creatinine: daytime, 2.51 ± 0.65; nighttime, 2.52 ± 0.71; p = 0.78). Circadian fluctuation of albuminuria and proteinuria occurred parallel to that of the U-AGT levels. U-AGT levels were significantly and positively correlated with the levels of BP and circadian fluctuation of U-AGT was correlated with diurnal BP changes. CONCLUSION: These data suggest that the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which are associated with diurnal BP variation.

The level of urinary α1 microglobulin excretion is a useful marker of peritubular capillaritis in antineutrophil cytoplasmic antibody associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis affects small vessels in the kidney (i.e., arterioles, glomerular or peritubular capillaries, or venules). Although crescentic glomerulonephritis is a common histological finding, the incidence of peritubular capillaritis (PTC) or arteriolitis is unclear. Moreover, the laboratory data that reflect the degree of renal histological damage and distinguish between PTC and arteriolitis have not yet been clarified. METHODS: We investigated laboratory data and histological findings from 11 patients diagnosed with ANCA-associated vasculitis (2 men and 9 women, mean age 70.3 ± 3.3 years) whose renal biopsies were performed between 2009 and 2014. RESULTS: All patients were positive for myeloperoxidase (MPO)-ANCA. PTC or arteriolitis was detected in six patients (54.5 %), respectively. The only significant positive relationship between laboratory data and histological findings observed was that between levels of urinary α1 microglobulin (u-α1MG) excretion and the percentage of tubular atrophy and interstitial fibrosis (r = 0.67, p = 0.035). No significant differences in laboratory data were found between patients with or without arteriolitis. However, the levels of u-α1MG excretion were significantly higher in patients with PTC than in those without PTC (75.2 ± 19.5 vs. 15.0 ± 3.6 mg/dl, p = 0.035). CONCLUSION: PTC or arteriolitis occurs at a high rate independently of crescentic glomerulonephritis in ANCA-associated vasculitis patients. The levels of u-α1MG excretion reflect the degrees of tubular atrophy and interstitial fibrosis. Moreover, high levels of u-α1MG excretion suggest that PTC is more likely than arteriolitis in ANCA-associated vasculitis patients.

Hyperuricaemia is associated with renal damage independently of hypertension and intrarenal renin-angiotensin system activation, as well as their circadian rhythms.

AIM: Both hyperuricaemia and activation of the intrarenal renin-angiotensin system (RAS) play an important role in the development of hypertension and renal damage. However, it has not been clear whether hyperuricaemia is associated with renal damage due to hypertension or intrarenal RAS activation, as well as their circadian rhythms. METHODS: We recruited 43 chronic kidney disease (CKD) patients who did not receive RAS blockers and antihyperuricaemic drugs, and investigated the relationship among serum uric acid (sUA) levels, the circadian rhythm of urinary angiotensinogen (U-AGT) excretion levels, and the levels of albuminuria (U-ACR) and proteinuria (U-P/Cr). RESULTS: sUA levels were significantly associated with estimated glomerular filtration rate (eGFR) (P = 0.002), systolic blood pressure (SBP) (daytime, P = 0.031), and U-ACR (daytime, P = 0.006 and nighttime, P = 0.008) and U-P/Cr (daytime, P = 0.017 and nighttime, P = 0.013). However, there were no significant differences between sUA levels and SBP in nighttime and U-AGT excretion levels in both time periods. Multiple regression analyses for sUA levels were performed using age, sex, eGFR and each parameter (SBP, U-AGT/Cr, U-ACR or U-P/Cr). sUA levels were not associated with SBP or U-AGT/Cr in both time periods. sUA levels tended to correlate with U-P/Cr levels in nighttime, and were significantly associated with U-P/Cr in daytime (P = 0.026) and U-ACR in daytime (P = 0.017) and nighttime (P = 0.046). Moreover, no significant differences were found between sUA levels and night-to-day ratios of some parameters. CONCLUSION: These data suggest that hyperuricaemia is associated with renal damage, independently of hypertension and intrarenal RAS activation, as well as their circadian rhythms.

Impact of Right Ventricular Geometry on Mitral Regurgitation After Transcatheter Closure of Atrial Septal Defect.

Worsening of mitral regurgitation (MR) is sometimes observed after closure of an atrial septal defect (ASD). However, since the mechanism of this deterioration remains unclear, the aim of our study was to investigate the effect of left (LV) and right ventricular (RV) geometry on MR after transcatheter closure of ASD.We studied 27 patients with ASD who underwent transcatheter closure. Echocardiography was performed before and 6 ± 2 months after the procedure. In addition to conventional echocardiographic parameters, full volume data of the whole LV and RV heart was obtained with 3-dimensional echocardiography. MR was quantified by measuring the width of the vena contracta, and was graded as mild (< 3.0 mm), moderate (3.0 to 6.9 mm), or severe (≥ 7.0 mm).Ten patients (37%) were classified as having worsening MR and the remaining 17 (63%) as not having worsening MR. The two groups showed similar baseline characteristics, except for patients with worsening MR being more likely to be older (P = 0.009) and having a larger left-to-right shunt of pulmonary and systemic blood flow ratio (P = 0.02). It is noteworthy that the horizontal-to-vertical ratio of basal-RV at end-systole for patients with worsening MR was significantly smaller than that for patients without worsening MR (1.0 ± 0.2 versus 1.4 ± 0.2, P < 0.0001). Furthermore, multivariate analysis showed that the horizontal-to-vertical ratio of basal-RV at end-systole was the independent predictor of worsening MR during follow-up (P < 0.001).RV geometry may affect MR after closure of ASD. The pre-operative horizontal-to-vertical ratio of basal-RV is considered useful for predicting worsening of MR after closure of ASD.

Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice.

Acute kidney injury (AKI) dramatically increases sepsis mortality, but AKI diagnosis is delayed when based on serum creatinine (SCr) changes, due in part, to decreased creatinine production. During experimental sepsis, we compared serum cystatin C (sCysC), SCr, and blood urea nitrogen (BUN) to inulin glomerular filtration rate (iGFR) before or 3-18 h after cecal ligation and puncture (CLP)-induced sepsis in CD-1 mice. sCysC had a faster increase and reached peak levels more rapidly than SCr in both sepsis and bilateral nephrectomy (BiNx) models. sCysC was a better surrogate of iGFR than SCr during sepsis. Combining sCysC with SCr values into a composite biomarker improved correlation with iGFR better than any biomarker alone or any other combination. We determined the renal contribution to sCysC handling with BiNx. sCysC and SCr were lower post-BiNx/CLP than post-BiNx alone, despite increased inflammatory and nonrenal organ damage biomarkers. Sepsis decreased CysC production in nephrectomized mice without changing body weight or CysC space. Sepsis decreased sCysC production and increased nonrenal clearance, similar to effects of sepsis on SCr. sCysC, SCr, and BUN were measured 6 h postsepsis to link AKI with mortality. Mice with above-median sCysC, BUN, or SCr values 6 h postsepsis died earlier than mice with below-median values, corresponding to a substantial AKI association with sepsis mortality in this model. sCysC performs similarly to SCr in classifying mice at risk for early mortality. We conclude that sCysC detects AKI early and better reflects iGFR in CLP-induced sepsis. This study shows that renal biomarkers need to be evaluated in specific contexts.