Activation of the intrarenal renin-angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. ...Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.
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.
The incidence of acute kidney injury (AKI) has increased as the population has aged 1. Aging is an independent risk factor for AKI 2. AKI that develops in the elderly is more severe and the patient ...is less likely to recover 3. Although AKI has emergent problems, there is no specific therapeutic agent and it is difficult to develop new drugs for AKI. KCI Citation Count: 1
Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults. Autoantibodies against M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A ...(THSD7A), which mainly belong to the IgG4 subclass, were reported as associated antibodies for the development of MN. Although PLA2R is a major target antigen for idiopathic MN, the prevalence of MN patients seropositive for PLA2R in Japan is lower than that in other countries. In this study, we conducted immunohistochemical analysis of the presence of THSD7A and PLA2R in renal specimens of MN patients to estimate the prevalence of THSD7A/PLA2R-related idiopathic MN in Japan. Enhanced granular expression of THSD7A and PLA2R was detected in 9.1% and 52.7%, respectively, of the patients with idiopathic MN. Although none of patients with secondary MN displayed enhanced granular expression of THSD7A, 5.4% of them had enhanced granular expression of PLA2R. In conclusion, the prevalence of enhanced granular expression of THSD7A in the glomeruli of Japanese patients with idiopathic MN was higher than the prevalence of MN patients seropositive for THSD7A in USA and Europe.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. We previously reported that the prevalence of phospholipase A2 receptor (PLA2R)- and thrombospondin type 1 domain ...containing 7A (THSD7A)-associated MN patients in Japan is 52.7% and 9.1%, respectively. In addition to PLA2R and THSD7A, we assessed the presence of newly discovered target antigens, neural epidermal growth factor-like 1 (NELL-1), semaphorin 3B (SEMA3B), and exostosin 1/exostosin 2 (Ext1/Ext2), in renal specimens from patients with primary and secondary MN by immunohistochemistry. We found enhanced glomerular staining of PLA2R, THSD7A, NELL-1, and Ext1/Ext2 in 53.6%, 8.7%, 1.5%, and 13.0% of the renal samples, respectively, in patients with primary MN. None of the patient specimens showed enhanced staining of SEMA3B. Enhanced glomerular staining of PLA2R, NELL-1, and Ext1/Ext2 was detected in 5.7%, 8.6%, and 22.9% of the patients with secondary MN, respectively. Based on our findings, we recommend the assessment of PLA2R, THSD7A and NELL-1 in addition to clinical information and IgG4 staining to differentiate between primary and secondary MN. This would aid in distinguishing secondary MN patients from primary MN patients who coincidentally have some secondary characteristics.
Circadian fluctuation disorder of the intrarenal renin-angiotensin system (RAS) causes that of blood pressure (BP) and renal damage. In renal damage with an impaired glomerular filtration barrier, ...liver-derived angiotensinogen (AGT) filtered through damaged glomeruli regulates intrarenal RAS activity. Furthermore, glomerular permeability is more strongly affected by glomerular hypertension than by systemic hypertension. Thus, we aimed to clarify whether the circadian rhythm of intrarenal RAS activity is influenced by AGT filtered through damaged glomeruli due to glomerular capillary pressure. Rats with adriamycin nephropathy and an impaired glomerular filtration barrier were compared with control rats. In adriamycin nephropathy rats, olmesartan medoxomil (an angiotensin II type 1 receptor blocker) or hydralazine (a vasodilator) was administered, and the levels of intrarenal RAS components in the active and rest phases were evaluated. Moreover, the diameter ratio of afferent to efferent arterioles (A/E ratio), an indicator of glomerular capillary pressure, and the glomerular sieving coefficient (GSC) based on multiphoton microscopy in vivo imaging, which reflects glomerular permeability, were determined. Mild renal dysfunction was induced, and the systemic BP increased, resulting in increased A/E ratios in the adriamycin nephropathy rats compared with the control rats. Fluctuations in intrarenal RAS activity occurred in parallel with circadian fluctuations in glomerular capillary pressure, which disappeared with olmesartan treatment and were maintained with hydralazine treatment. Furthermore, the GSCs for AGT also showed similar changes. In conclusion, intrarenal RAS activity is influenced by the filtration of liver-derived AGT from damaged glomeruli due to circadian fluctuation disorder of the glomerular capillary pressure.
Abstract
Background
Cisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) ...inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI.
Methods
In in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay.
Results
In in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-α expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG.
Conclusions
The DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients.
Cisplatin is a highly effective chemotherapeutic agent. However, acute kidney injury (AKI) limits its subsequent use, resulting in poor cancer prognosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors ...have been reported to attenuate cisplatin-induced AKI in animal models, but the effect in human patients remains to be clarified. We hypothesized that DPP-4 inhibitors can prevent cisplatin-induced AKI in diabetic-cancer patients.
We retrospectively reviewed all consecutive cancer patients who were treated with a first cycle of cisplatin-containing regimen between January 2011 and October 2019. We analysed data of diabetic-cancer patients treated with high-dose cisplatin (> 50 mg/m2)-containing regimens. The change of estimated glomerular filtration rate (eGFR) within 2 weeks after cisplatin treatment was compared between the patients treated with DPP-4 inhibitors and those treated without DPP-4 inhibitors.
A total of 455 patients were treated with cisplatin during the period. Of these, 34 patients were eligible for the analysis. The change of eGFR was significantly less in the patients treated with DPP-4 inhibitors, compared to those without DPP-4 inhibitors the percentages of eGFR decline (mean ± SD) was 23.6 ± 20.3% vs 43.1± 20.1%, respectively; P = 0.010. Furthermore, the incidence of AKI was significantly less in the patients treated with DPP-4 inhibitors (25% vs 64%, respectively; P = 0.026).
DPP-4 inhibitors may decrease the risk of cisplatin-induced AKI in diabetic patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Sarcoidosis is a systemic disease that can affect multiple organs. While pulmonary sarcoidosis is most commonly observed, renal sarcoidosis occurs less frequently. We herein ...report a case of sarcoidosis with an exceptionally rare distribution including renal lesions. Case presentation A 51-year-old Japanese female was referred because of bilateral parotid swelling and renal dysfunction. Computed tomography scan showed the swelling of bilateral kidneys, parotid glands, and uterus. Ga scintigraphy also showed remarkable accumulation in these organs. Renal biopsy and cytological evaluations of parotid gland and uterus were performed and she was diagnosed as sarcoidosis of these organs. Treatment was initiated with prednisolone 40 mg/day and then renal dysfunction subsequently improved. In addition, the swelling of parotid glands and uterus improved and Ga accumulation in each organ had disappeared. Conclusion This is a first case of renal sarcoidosis complicated by parotid glands and uterus lesions. Pathological findings and the reactivity observed in Ga scintigraphy indicated the presence of lesions in these organs.
A percutaneous renal biopsy (PRB) is a standard procedure for diagnosing renal disease, but can cause bleeding complications. Bleeding after a PRB can be classified as early- or late-onset, depending ...on the timing of the onset of the bleeding symptoms (<24 h or ≥24 h). We herein report two patients who experienced bleeding complications: one experienced early-onset bleeding from the 12th subcostal artery, and the other experienced late-onset bleeding from an arteriovenous fistula between a branch of the renal artery and renal vein. In both cases, the origin of the bleeding vessel was misjudged during the first examination. We discuss the diagnostic pitfalls of the origin of bleeding after a PRB and propose measures to avoid falling such pitfalls.A percutaneous renal biopsy (PRB) is a standard procedure for diagnosing renal disease, but can cause bleeding complications. Bleeding after a PRB can be classified as early- or late-onset, depending on the timing of the onset of the bleeding symptoms (<24 h or ≥24 h). We herein report two patients who experienced bleeding complications: one experienced early-onset bleeding from the 12th subcostal artery, and the other experienced late-onset bleeding from an arteriovenous fistula between a branch of the renal artery and renal vein. In both cases, the origin of the bleeding vessel was misjudged during the first examination. We discuss the diagnostic pitfalls of the origin of bleeding after a PRB and propose measures to avoid falling such pitfalls.
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