Chronic Kidney Inflammation Research Articles

Itaconate Serves as a Urinary Biomarker and an Inhibitor of Chronic Kidney Inflammation

Itaconate Serves as a Urinary Biomarker and an Inhibitor of Chronic Kidney Inflammation

Dihydromyricetin ameliorates diabetic renal fibrosis via regulating SphK1 to suppress the activation of NF-κB pathway

Dihydromyricetin (DHM) is a flavonoid from vine tea with broad pharmacological benefits, which improve inflammation by blocking the NF-κB pathway. A growing body of research indicates that chronic kidney inflammation is vital to the pathogenesis of diabetic renal fibrosis. Sphingosine kinase-1 (SphK1) is a key regulator of diabetic renal inflammation, which triggers the NF-κB pathway. Hence, we evaluated whether DHM regulates diabetic renal inflammatory fibrosis by acting on SphK1. Here, we demonstrated that DHM effectively suppressed the synthesis of fibrotic and inflammatory adhesion factors like ICAM-1, and VCAM-1 in streptozotocin-treated high-fat diet-induced diabetic mice and HG-induced glomerular mesangial cells (GMCs). Moreover, DHM significantly suppressed NF-κB pathway activation and reduced SphK1 activity and protein expression under diabetic conditions. Mechanistically, the results of molecular docking, molecular dynamics simulation, and cellular thermal shift assay revealed that DHM stably bound to the binding pocket of SphK1, thereby reducing sphingosine-1-phosphate content and SphK1 enzymatic activity, which ultimately inhibited NF-κB DNA binding, transcriptional activity, and nuclear translocation. In conclusion, our data suggested that DHM inhibited SphK1 phosphorylation to prevent NF-κB activation thus ameliorating diabetic renal fibrosis. This supported the clinical use and further drug development of DHM as a potential candidate for treating diabetic renal fibrosis.

Polydatin attenuates diabetic renal inflammatory fibrosis via the inhibition of STING pathway

Diabetic nephropathy (DN) is a complication of diabetes and is mainly characterized by renal fibrosis, which could be attributed to chronic kidney inflammation. Stimulator of interferon genes (STING), a linker between immunity and metabolism, could ameliorate various metabolic and inflammatory diseases. However, the regulatory role of STING in DN remains largely unexplored. In this study, knockdown of STING decreased extracellular matrix (ECM), pro-inflammatory, and fibrotic factors in high glucose (HG)-induced glomerular mesangial cells (GMCs), whereas overexpression of STING triggered the inflammatory fibrosis process, suggesting that STING was a potential target for DN. Polydatin (PD) is a glucoside of resveratrol and has been reported to ameliorate DN by inhibiting inflammatory responses. Nevertheless, whether PD improved DN via STING remains unclear. Here, transcriptomic profiling implied that the STING/NF-κB pathway might be an important target for PD. We further found that PD decreased the protein expression of STING, and subsequently suppressed the activation of downstream targets including TBK1 phosphorylation and NF-κB nuclear translocation, and eventually inhibited the production of ECM, pro-inflammatory and fibrotic factors in HG-induced GMCs. Notably, results of molecular docking, molecular dynamic simulations, surface plasmon resonance, cellular thermal shift assay and Co-immunoprecipitation assay indicated that PD directly bound to STING and restored the declined proteasome-mediated degradation of STING induced by HG. In diabetic mice, PD also inhibited the STING pathway and improved the pathological changes of renal inflammatory fibrosis. Our study elucidated the regulatory role of STING in DN, and the novel mechanism of PD treating DN via inhibiting STING expression.

Galantamine Reduces Blood Pressure and Renal Injury in Female Angiotensin II-induced Hypertensive Mice

Inflammation is a known culprit in the development and progression of hypertension. The autoimmune disease, systemic lupus erythematosus (SLE), is an important model of hypertension in the setting of chronic kidney inflammation. We have shown that administration of an acetylcholinesterase inhibitor, galantamine, attenuates the hypertension, kidney inflammation, and kidney injury in female SLE mice by activating the vagally-mediated cholinergic anti-inflammatory pathway. Although SLE hypertension represents a specific population of patients, we hypothesized that galantamine would have similar anti-inflammatory effects in the angiotensin II (AngII)-induced hypertensive mouse, which more commonly models essential hypertension. Female C57BL/6 mice were implanted with minipumps at 9 weeks of age for subcutaneous delivery of either AngII (1000 ng/kg/min) or saline (controls), and galantamine hydrobromide (4 mg/kg/day) or vehicle, for 21 days. At 12 weeks, carotid catheters were implanted and mean arterial pressure (MAP) was measured in conscious mice for two consecutive days. Mice were then euthanized, and kidneys collected. Markers of kidney inflammation and injury, including interleukin (IL)-6 and kidney injury molecule (KIM)-1, were measured by ELISA and normalized to total kidney protein. MAP (mmHg) was higher in AngII-treated mice compared to controls (174±4 vs. 133±3; n=4-5, p=0.0023). Galantamine lowered MAP in AngII mice (157±8; n=7, p=0.2567) without altering MAP in controls (133±4; n=5, p=0.9999). Renal IL-6 (pg/μg) was not different between AngII and control mice (0.004±0.0001 vs. 0.005±0.0006; p=0.6685). Although galantamine lowered IL-6 in both groups, it was only significant in controls (0.003±0.0002; p=0.0134) and not AngII mice (0.003±0.0003; p=0.4677). Renal cortical KIM-1 (pg/μg) trended higher in AngII mice compared to controls (2.53±0.50 vs 0.63±0.16; p=0.0741). Galantamine lowered KIM-1 in AngII mice (1.18±0.39, p=0.2064), but not controls (1.45 ± 0.59; p=0.6285). In summary, galantamine protected female mice from hypertension and renal injury in a model of AngII hypertension. This suggests that acetylcholinesterase inhibitor therapy may be effective in patients with hypertension. Studies funded by NIH R01HL153703 and K01HL139859 for KWM. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ecofriendly appraisal of stability-indicating high-performance chromatographic assay of canagliflozin and metformin with their toxic impurities; in silico toxicity prediction.

Canagliflozin is an oral hypoglycemic drug recently formulated in combination with a biguanide, metformin hydrochloride, for improving its hypoglycemic action. Canagliflozin has one reported major degradation product, also metformin hydrochloride has one reported major degradation product, cyanoguanidine, and has a potential toxic impurity, melamine, that is reported to cause crystalluria that causes chronic kidney inflammation and nephrolithiasis leading to a renal failure. As per International Conference of Harmonization guidelines; a drug degradation product is classified as a type of drug impurities. Toxicity profiles of canagliflozin and metformin major degradation products were studied where in silico data disclosed toxicity too; the development of a specific chromatographic thin layer chromatographic assay was a must for quantification of such toxic related components along with the drugs in laboratory-prepared mixtures as a superior study. The proposed method was validated as per the International Conference of Harmonization and applied for the assay of Vokanamet tablets. The separation was achieved using acetone:ethyl acetate:acetic acid (8:2:0.2, by volume) as scanning eluted bands at 205 nm. For minimal environmental impact; greenness profile appraisal of the proposed assay was performed by three greenness assessment approaches; analytical Eco-Scale, Green Analytical Procedure Index, and Greenness metric approaches.

Xanthogranulomatous Pyelonephritis- A Series of two Cases and a Review of the Literature

Xanthogranulomatous pyelonephritis (XGP) is a rare and severe manifestation of chronic kidney inflammation that can be critical if not recognized and treated appropriately, often requires surgical intervention along with antibiotics. Most commonly presented in the fifth or sixth decade of life with a prior history of nephrolithiasis, obstructive uropathy, or recurrent urinary tract infections. Here, we discuss a 45-year-old male and a 73-year-old female who came with abdominal pain and weight loss for two months. An enlarged and distorted renal outline, with altered echotexture and calculus in renal pelvis was revealed on ultrasound examination. Abdominal computed tomography revealed staghorn renal calculi and thinning of renal cortex with involvement of adjacent structures.

Management and Prevention of Sarcopenia in Era Covid-19

Xanthogranulomatous pyelonephritis (XGP) is a rare and severe manifestation of chronic kidney inflammation that can be critical if not recognized and treated appropriately, often requires surgical intervention along with antibiotics. Most commonly presented in the fifth or sixth decade of life with a prior history of nephrolithiasis, obstructive uropathy, or recurrent urinary tract infections. Here, we discuss a 45-year-old male and a 73-year-old female who came with abdominal pain and weight loss for two months. An enlarged and distorted renal outline, with altered echotexture and calculus in renal pelvis was revealed on ultrasound examination. Abdominal computed tomography revealed staghorn renal calculi and thinning of renal cortex with involvement of adjacent structures.

Using R in Regulatory Toxicology.

Statistical analyses are an essential part of regulatory toxicological evaluations. While projects would be ideally monitored by both toxicologists and statisticians, this is often not possible in practice. Hence, toxicologists should be trained in some common statistical approaches but also need a tool for statistical evaluations. Due to transparency needed in regulatory processes and standard tests that can be evaluated with template approaches, the freely available open-source statistical software R may be suitable. R is a well-established software in the statistical community. The principal input method is via software code, which is both benefit and weakness of the tool. It is increasingly used by regulating authorities globally and can be easily extended by software packages, e.g., for new statistical functions and features. This manuscript outlines how R can be used in regulatory toxicology, allowing toxicologists to perform all regulatory required data evaluations in a single software solution. Practical applications are shown in case studies on simulated and experimental data. The examples cover a) Dunnett testing of treatment groups against a common control and in relation to a biological relevance threshold, assessing the test's assumptions and plotting the results; b) dose-response analysis and benchmark dose derivation for chronic kidney inflammation as a function of Pyridine; and c) graphical/exploratory data analysis of previously published developmental neurotoxicity data for Chlorpyrifos.

Abstract 10313: Gender and Strain Background Affect Cardiopulmonary Function in Col4a3 -/- Alport Mice

Background: Alport syndrome (AS) is a hereditary form of chronic kidney inflammation that results in renal failure (RF). We previously reported that Col4a3 -/- 129J mice, a model of AS and RF, exemplified multiple features of heart failure with preserved ejection fraction (HFpEF). This study investigates the effect of 3 different genetic backgrounds on cardiopulmonary function in Col4a3 -/- mice. Methods: Male and female Col4a3 -/- (Alport) and WT mice from 129x1/SvJ, C57Bl/6 and BALBC strain were examined using echocardiography, whole body plethysmography (WBP) and pressure-volume (PV) loop analysis. Ttest was used for statistical analysis. Four groups per strain were used (n= 4-15/group). Results: Compared with their respective age-matched WT controls, male and female 8-week-old Col4a3 -/- 129x1/SvJ mice demonstrated impaired systolic function (EF of 56 to 43.7%, p=.002 for females and 50.9 to 42% for males, p=.044; SV, CO, p<.05) and diastolic dysfunction (increased IVRT from 15.3 to 21.7ms, p=.0009 for females; 16.6 to 26.2ms, p<.0001 for males; increased MPI, P<.05). Additionally, PV loop analysis showed an increased EDPVR and end diastolic pressure, prolonged time constant of LV relaxation, and decreased CO and SV (p<0.05). For Col4a3 -/- BalbC and Col4a3 -/- C57Bl/6 strains, only females exhibited systolic (BalbC: EF% 51 to 45.66%, p=0.106 for females and 43.5 to 40.8% for males, p=.51; B6: EF% 51.3 to 40.8% p=.02 for females and 48.4 to 40.9%, p=.31 for males; SV, CO, p<.05) and diastolic dysfunction (IVRT from 16 to 24.1ms for BalbC and 18.20 to 25.63ms for B6, p<0.05). Male Col4a3 -/- BalbC had an increase in minimum and end-systolic pressures, and an increased pressure at dV/dt-max. Male Col4a3 -/- C57Bl/6 mice had an increased ESPVR slope (p<.05). All strains except BalbC males demonstrated alterations (p<.05) in pulmonary function including decreased ventilation rate (MV) and respiratory frequency, decreased peak expiratory flow, EF50, increased expiratory time, relaxation time, inspiratory time, and time of pause at end-of-expiration. Conclusion: Both male and female Col4a3 -/- 129x1/SvJ mice demonstrated impaired cardiopulmonary viability. However, Col4a3 -/- mice on BalbC or C57Bl/6 strains had cardiopulmonary deficits only in females.

The cell membrane repair protein MG53 modulates transcription factor NF-κB signaling to control kidney fibrosis

Kidney fibrosis is associated with the progression of acute kidney injury to chronic kidney disease. MG53, a cell membrane repair protein, has been shown to protect against injury to kidney epithelial cells and acute kidney injury. Here, we evaluated the role of MG53 in modulation of kidney fibrosis in aging mice and in mice with unilateral ureteral obstruction (UUO) a known model of progressive kidney fibrosis. Mice with ablation of MG53 developed more interstitial fibrosis with age than MG53-intact mice of the same age. Similarly, in the absence of MG53, kidney fibrosis was exaggerated compared to mice with intact MG53 in the obstructed kidney compared to the contralateral unobstructed kidney or the kidneys of sham operated mice. The ureteral obstructed kidneys from MG53 deficient mice also showed significantly more inflammation than ureteral obstructed kidneys from MG53 intact mice. Invitro experiments demonstrated that MG53 could enter the nuclei of proximal tubular epithelial cells and directly interact with the p65 component of transcription factor NF-κB, providing a possible explanation of enhanced inflammation in the absence of MG53. To test this, enhanced MG53 expression through engineered cells or direct recombinant protein delivery was given to mice subject to UUO. This reduced NF-κB activation and inflammation and attenuated kidney fibrosis. Thus, MG53 may have a therapeutic role in treating chronic kidney inflammation and thereby provide protection against fibrosis that leads to the chronic kidney disease phenotype.

Abstract P390: Gender And Strain Background Affect Cardiopulmonary Function In Col4a3 -/- Alport Mice

Background: Alport syndrome (AS) is a hereditary form of chronic kidney inflammation that results in renal failure (RF). Our group previously reported that Col4a3 -/- mice, a model of AS and RF, on 129J background exemplified multiple features of heart failure with preserved ejection fraction (HFpEF). This study investigates the effect of 3 different genetic backgrounds on cardiopulmonary function in Col4a3 -/- mice. Methods: Male and female Col4a3 -/- (Alport) and WT mice on 3 different genetic backgrounds, 129x1/SvJ, C57Bl/6 and BALBC, were examined using echocardiography, whole body plethysmography (WBP) and pressure-volume (PV) loop analysis. Ttest was used for statistical analysis. Four groups per strain were used (n= 4 to 15 per group). Results: Compared with their respective age-matched WT controls, both male and female 8-week-old Col4a3 -/- 129x1/SvJ mice demonstrated impaired systolic function (EF of 56% to 43.7%, p=0.0018 for females and 50.9% to 42% for males, p=0.044; SV, CO, p<0.05) and diastolic dysfunction (increased IVRT from 15.32ms to 21.72ms, p=0.0009 for females; 16.57ms to 26.21ms, p<0.0001 for males; increased MPI, P<0.05). Additionally, PV loop analysis showed an increased EDPVR and end diastolic pressure, prolonged time constant of LV relaxation, and decreased CO and SV (p<0.05). However for Col4a3 -/- BalbC (8-week-old) and Col4a3 -/- C57Bl/6 (20-week-old) strains, only females exhibited systolic (BalbC: EF% 51% to 45.66%, p=0.106 for females and 43.5% to 40.8% for males, p=0.508; B6: EF% 51.30% to 40.80% p=0.024 for females and 48.43% to 40.91%, p=0.3098 for males; SV, CO, p<0.05) and diastolic dysfunction (IVRT from 15.96ms to 24.91ms for Balb/C and 18.20ms to 25.63ms for B6, p<0.05). Male Col4a3 -/- BalbC had an increase in minimum pressure and end-systolic pressure, and an increased pressure at dV/dt-max. Male Col4a3 -/- C57Bl/6 mice had an increased ESPVR slope (p<0.05). All strains except BalbC males demonstrated alterations (p<0.05) in pulmonary function including decreased ventilation rate (MV, mL/min) and respiratory frequency (BPM), decreased peak expiratory flow, EF50, increased expiratory time, relaxation time, inspiratory time, and time of pause at end-of-expiration. Conclusion: Both male and female Col4a3 -/- 129x1/SvJ mice demonstrated impaired cardiopulmonary viability. However, Col4a3 -/- mice on BalbC or C57Bl/6 strains had cardiopulmonary deficits only in females.

DNA Methylation Sustains “Inflamed” Memory of Peripheral Immune Cells Aggravating Kidney Inflammatory Response in Chronic Kidney Disease

The incidence of chronic kidney disease (CKD) has rapidly increased in the past decades. A progressive loss of kidney function characterizes a part of CKD even with intensive supportive treatment. Irrespective of its etiology, CKD progression is generally accompanied with the development of chronic kidney inflammation that is pathologically featured by the low-grade but chronic activation of recruited immune cells. Cumulative evidence support that aberrant DNA methylation pattern of diverse peripheral immune cells, including T cells and monocytes, is closely associated with CKD development in many chronic disease settings. The change of DNA methylation profile can sustain for a long time and affect the future genes expression in the circulating immune cells even after they migrate from the circulation into the involved kidney. It is of clinical interest to reveal the underlying mechanism of how altered DNA methylation regulates the intensity and the time length of the inflammatory response in the recruited effector cells. We and others recently demonstrated that altered DNA methylation occurs in peripheral immune cells and profoundly contributes to CKD development in systemic chronic diseases, such as diabetes and hypertension. This review will summarize the current findings about the influence of aberrant DNA methylation on circulating immune cells and how it potentially determines the outcome of CKD.

Age-Related Physiological and Pathophysiological Features of the Masticatory Apparatus in Adults

Age-related physiological and pathophysiological features of the masticatory apparatus were studied via electrodontometry, estesiometry, electrogustometry, and the determination of thresholds and functional mobility of taste receptors of the tongue. The study was based on an evaluation of the condition of organs and tissues of the masticatory apparatus in 275 (69 men and 206 women) individuals aged from 25 to 86 years, including 74 elderly and senile individuals suffering from diabetes mellitus type 2, chronic nonspecific inflammatory bowel diseases, alcoholism, and chronic kidney disease. It was found that the thresholds of pain sensitivity of teeth, oral mucosa, and the tongue and taste sensitivity increase with age, while the functional mobility of taste receptors becomes impaired. The presence in elderly and senile individuals of psychosomatic pathology, especially type-2 diabetes, chronic kidney disease, and chronic alcoholism in older age groups, exacerbates existing age-related changes in pain and taste sensitivity and leads to severe disorders in the directed response of taste receptors. The indicators presented in this paper, which characterize some age-related physiological and pathophysiological features of the masticatory apparatus in elderly and senile individuals, can be used as a starting point to study the degree of functional disorders of the masticatory apparatus and to take into account the degree of normalization of impaired functions in the treatment of individuals of older age groups.

P0996THE INVOLVEMENT OF PRO-INFLAMMATORY IL-1 CYTOKINES IN TUBULAR INJURY IN DIABETIC KIDNEY DISEASE

Abstract Background and Aims Pro-inflammatory cytokines are one of several factors which contribute to the progression of diabetic kidney disease (DKD), a condition characterized by chronic kidney inflammation which results in the tubulointerstitial fibrosis which contributes to the progression of DKD. Interleukin 1 (IL-1) two main agonists IL-1α and IL-1β activate a pro-inflammatory cascade in response to different inflammatory stimuli, including hyperglycemia. It was previously shown that a deficiency of NLRP3 which is required for the conversion of IL-1 to its active state, protects mice from the development and progression of DKD. We hypothesize that the chronic hyperglycemia in diabetic patients triggers the activation and release of IL1α and/or IL-1β from renal tubular cells and that this activation leads to the tissue fibrosis. We aim to assess Il-1 and fibronectin expression in an immortalized proximal tubule epithelial cell line from normal adult human kidney (HK-2). In addition, we evaluate the influence of Anakinra™, a pharmaceutical inhibitor of the Il-1 receptor, currently indicated mainly for rheumatoid diseases, on the levels of fibronectin expression in this model. Methods HK-2 cells were cultured and treated with either physiological glucose concentration (5.5mM), high glucose (30mM) or 30mM mannitol as osmotic control for 24 hours to evaluate their effects on Il-1 expression and fibronectin expression. mRNA levels of IL-1α, IL-1β and fibronectin were assessed in q-PCR, and protein expression levels were quantified by western blotting. Immunofluorescence was used to visually demonstrate the presence of IL-1α and IL-1β upon stimulation. Finally, Anakinra™ was added to the tissue cultures in a range of physiologic prescribed concentrations and its effect on cell fibrosis was assessed by the measurement of fibronectin expression 24 hours later by western blotting. Results mRNA and protein expression of IL-1α but mostly IL-1β was elevated in HK-2 cells under hyperglycemic conditions but not in physiological glucose environment or under high osmotic conditions. Fibronectin levels were elevated in the high glucose treated cells compared with control. Finally, Anakinra™ was found to attenuate fibronectin expression under high glucose conditions, compared with the untreated cells. Conclusion Proinflammatory IL-1α and IL-1β cytokines are expressed by HK-2 cells upon stimulation with glucose and result in the fibrosis on the cells measured by the production of fibronectin. The addition of Anakinra™, an IL-1 receptor blocker, to the cell culture attenuate the expression of fibronectin by the tubular cells. Our research is the first to describe a causation between hyperglycemia, IL-1 elevated levels and fibrosis in HK-2 cells, as demonstrated by the beneficial effect of Anakinra™ on lowering fibronectin expression.

Pyelonephritis Xanthogranulomatosa – case report (2 cases)

Pyelonephritis xantogranulomatosa is a very rare form of chronic kidney inflammation. Only a few hundred cases have been described in children. The cause of the disease is not fully understood, but it is strongly correlated with urolithiasis. The inflammatory process usually involves one kidney and is diffuse, rarely a form limited to the part of the parenchyma is seen. The most common symptoms are abdominal pain, fever, weight loss, lack of appetite. In imaging tests the kidney is enlarged, with a preserved shape, contains deposits in the calyx and pelvic system and numerous hypoechogenic changes indicating abscesses. The most frequently isolated pathogens are E. coli and P. Mirabillis . The authors present 2 cases treated in our center due to Pyelonephritis xantogranulomatosa. In both cases a nephrectomy was performed.

Radiofrequency Renal Denervation Decreases Fibrosis in Kidney Cortex and Medulla in Spontaneously Hypertensive Rats (SHR)

There are over 8.3 million people in the US that have chronic kidney disease (CKD), which ultimately can progress to end stage renal fibrosis. Despite an increasing prevalence of CKD, there are no new therapies targeting fibrosis. Our previous studies showed that removal of the renal nerves by radiofrequency renal denervation (RF‐RDN) decreases blood pressure, sympathetic activity, and renal inflammation in hypertensive SHR. Renal fibrosis is a common consequence of chronic kidney inflammation. Therefore, these studies investigated whether RF‐RDN will attenuate renal fibrosis in hypertensive SHR. 22‐week old SHR (n=7/group) received bilateral RF‐RDN or Sham‐RDN (Biosense Webster Stockert 70 generator and RF‐probe). Four weeks later, rat kidneys from all animals were harvested and paraffin sections were stained for fibrosis by Masson's trichrome staining. A pathologist, who was blinded to treatment groups, evaluated each kidney section for fibrosis. The results showed that Sham‐RDN treated SHR had extensive fibrosis demonstrated by moderate thickening of Bowman's capsule, collagen deposition in glomerulus, extensive tubulointerstitial fibrosis, and segmental glomerulosclerosis. In contrast, RF‐RDN significantly reduced each of these pathological components of fibrosis in kidney cortex and medulla. Chemokines play a critical role in mediating the infiltration of immune cells and subsequent fibrosis formation. Therefore, in other studies we measured (ELISA) expression levels of Chemokine ligand 5 (CCL5), CCL2 and CXCL16 in kidney homogenates from RF‐RDN or Sham‐RDN SHR. RF‐RDN decreased CCL5 expression in kidney of SHR compared to Sham‐RDN (78.9±1.7 vs 87.9±2.7 pg/mg protein). RF‐RDN did not alter CCL5 expression in normotensive WKY (68.0±2.2 vs 68.4±3.3 pg/mg protein). These findings suggest that RF‐RDN may offer a novel therapy for renal fibrosis and CCL5 may serve as a potential therapeutic target to treat CKD.Support or Funding InformationNIGMS of NIH U54 GM104940 LA CaTS Roadmap Scholar to JG. NIH P30GM106392 to DRK & Pilot project to JG.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Natural killers: the bad guys in fibrosis?

Immune cells infiltrating the tubulointerstitium critically contribute to the progression of chronic kidney disease. In this issue of Kidney international, Law etal. provide first evidence for a role of natural killer cells in the perpetuation of tubulointerstitial fibrosis in human renal disease. By detailed flow cytometric characterization of leukocytes isolated from kidney biopsies of chronic kidney disease patients, they define accumulation of natural killer cells as a feature of fibrotic kidney tissue and provide insight into potential mechanisms of how these cells might promote chronic kidney inflammation.

Xanthogranulomatous pyelonephritis presenting as acute pleuritic chest pain: a case report

BackgroundXanthogranulomatous pyelonephritis is a rare and serious manifestation of chronic kidney inflammation that can be life-threatening if not recognized and treated appropriately, often with antibiotics and surgery. Affected patients are most commonly females in their fifth or sixth decade of life with a background of obstructive uropathy, nephrolithiasis, or recurrent urinary tract infections who present with vague nonspecific symptoms.Case presentationA 43-year-old woman of Russian ethnicity with a history of nephrolithiasis presented to our emergency department with new left-sided pleuritic chest pain amid a 6-week history of constitutional symptoms including fevers, night sweats, and 7 kg of weight loss. Workup for acute coronary syndrome and pulmonary embolism in our emergency department was negative. Given that she was clinically unwell, she was admitted to internal medicine to expedite workup for the cause of her symptoms. A broad differential diagnosis for various infectious, inflammatory/autoimmune, and neoplastic processes was considered. Based on classic radiographic and histopathologic findings, she was ultimately diagnosed with xanthogranulomatous pyelonephritis of her left kidney, which was a direct consequence of chronic inflammation. This inflammation exhibited spread to local tissues and across her left hemidiaphragm, resulting in a unilateral pleural effusion which explained her chest discomfort. She was treated with antibiotics administered intravenously and urgent total nephrectomy with a good functional outcome.ConclusionsOur case illustrates an uncommon but clinically important do-not-miss diagnosis that underlies a common clinical presentation of pleuritic chest pain. The case underscores the importance of maintaining a broad differential diagnosis and organized approach when treating patients with undifferentiated clinical presentations.

Locul şI rolul rifaximinei-α în tratamentul diareei călătorului

Traveler’s diarrhea (TD) is an acute, self-limited disease, caused by a wide array of germs that possess intestinal tropism. Among the 12 million people travelling annually to tropical or subtropical areas, 30% up to 70% are affected by TD. A single episode of diarrhea can severely impair, sometimes severe, the performance of special categories of travelers, like sportsmen, business people, or diplomats in specific missions. The disease has an equal distribution among sexes, occurring with a higher frequency among the youth. The Enterotoxigenic E.coli is the main pathogen incriminated in 80 to 90% of TD’cases. Recent international infectious disease or traveler medicine guidelines are recommending Rifaximine-α(RFX) as the first therapeutical option with the highest level of recommendation and evidence (IA) in treating or preventing non-invasive forms of TD. The normal daily dosage in these cases is 800 mg of RFX for at least 3 days. RFX is a non-absorbable (intestinal) antibiotic which has clinically proven its high rate of success regarding its safety and efficacy in treating and preventing TD. Referring to TD’s prevention, it must be mentioned that even though antibiotic prophylaxis is not routinely recommended while travelling (at least in cases of more than 3 weeks of travel), this approach should be serious taken into consideration for several types of high risk traveler patients who present at least one of the following conditions: immunodeficiency, chronic inflammatory intestinal diseases, kidney failure or diabetes mellitus. But even there are or not real reasons in recommending antibiotic prophylaxis, Rifaximine-α should not miss from any personal first-aid traveler-kit.

Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors.

Kidney fibrosis is the final common pathway for virtually every type of chronic kidney disease and is a consequence of a prolonged healing response that follows tissue inflammation. Chronic kidney inflammation ultimately leads to progressive tissue injury and scarring/fibrosis. Several pathways have been implicated in the progression of kidney fibrosis. In the present study, we demonstrate that G protein-coupled chemokine (C-X-C motif) receptor (CXCR)4 was significantly upregulated after renal injury and that sustained activation of Cxcr4 expression augmented the fibrotic response. We demonstrate that after unilateral ureteral obstruction (UUO), both gene and protein expression of Cxcr4 were highly upregulated in tubular cells of the nephron. The increased Cxcr4 expression in tubules correlated with their increased dedifferentiated state, leading to increased mRNA expression of platelet-derived growth factor (PDGF)-α, transforming growth factor (TGF)-β1, and concurrent loss of bone morphogenetic protein 7 (Bmp7). Ablation of tubular Cxcr4 attenuated UUO-mediated fibrotic responses, which correlated with a significant reduction in PDGF-α and TGF-β1 levels and preservation of Bmp7 expression after UUO. Furthermore, Cxcr4(+) immune cells infiltrated the obstructed kidney and further upregulate their Cxcr4 expression. Genetic ablation of Cxcr4 from macrophages was protective against UUO-induced fibrosis. There was also reduced total kidney TGF-β1, which correlated with reduced Smad activation and α-smooth muscle actin levels. We conclude that chronic high Cxcr4 expression in multiple effector cell types can contribute to the pathogenesis of renal fibrosis by altering their biological profile. This study uncovered a novel cross-talk between Cxcr4-TGF-β1 and Bmp7 pathways and may provide novel targets for interrupting the progression of fibrosis.