Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury

Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. In this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. In conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN.

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Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10

Frontiers in Pharmacology ◽

10.3389/fphar.2021.600163 ◽

2021 ◽

Vol 12 ◽

Author(s):

Naureen Fatima ◽

Sanket Patel ◽

Tahir Hussain

Keyword(s):

Renal Function ◽

Renal Injury ◽

Kidney Injury ◽

Cytokine Profile ◽

Antibody Treatment ◽

Tnf Α ◽

Anti Inflammatory ◽

Pre Treatment ◽

Anti Inflammation

Acute kidney injury (AKI) due to endotoxemic insult is predicted by the infiltration of neutrophils, monocytes and macrophages, and the release of pro-and anti-inflammatory cytokines to the site of injury. Earlier, we have demonstrated the role of angiotensin-II type 2 receptor (AT2R) stimulation in reno-protection in lipopolysaccharide (LPS)-induced inflammation and AKI in C57BL6/NHsd mice. Moreover, AT2R activation has been shown to increase the anti-inflammatory cytokine interleukin-10 (IL-10), its role in AT2R-mediated anti-inflammation and reno-protection is unknown. To address this question, in the present study mice were treated with the AT2R agonist C21 (0.3 mg/kg, intraperitoneally), LPS (5 mg/kg, intraperitoneally), or LPS with C21 pre-treatment with or without neutralizing IL-10 antibody. Treatment with C21 alone caused an increase in the plasma and kidney IL-10 levels, which peaks at 2-h, and returned to baseline at 6-h. The C21-induced IL-10 increase was blocked by the AT2R antagonist PD123319 suggesting AT2R’s involvement. LPS treatment caused a profound increase in tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the LPS-induced increase in these cytokines was attenuated by the C21 pre-treatment (1-h prior LPS) both in the plasma and kidney. Neutralizing IL-10 antibody treatment abrogated the C21-lowering of TNF-α and IL-6 in the kidney but not in the plasma. Similar results as related to the cytokines profiles in all the groups were also observed in the heart and spleen. The alteration in early cytokine profile prompted us to measure the markers of renal function (blood urea nitogen and urinary creatinine) in order to analyze the effect of IL-10 neutralization. However, it was too early to observe changes in renal function. Therefore, the renal function and injury markers were again measured at 24 h. Treatment with neutralizing IL-10 antibody attenuated the C21-mediated improvement in indices of the kidney function, but not the biomarkers of renal injury (kidney injury molecule-1 and neutrophil-gelatinase associated lipocalin). Collectively, our data suggest that the involvement of IL-10 in AT2R-mediated anti-inflammation and reno-protection against LPS is complex, mediating the renal cytokine profile and kidney filtration function, but not the plasma cytokine profile and renal injury markers.

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Acute interstitial nephritis and drug-induced systemic lupus erythematosus due to chlorthalidone and amiodarone: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x20910029 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2091002 ◽

Cited By ~ 1

Author(s):

Umut Selamet ◽

Ramy M Hanna ◽

Anthony Sisk ◽

Lama Abdelnour ◽

Lena Ghobry ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Interstitial Nephritis ◽

Lupus Erythematosus ◽

Kidney Biopsy ◽

Kidney Injury ◽

Acute Interstitial Nephritis ◽

Systemic Lupus ◽

Drug Induced ◽

Systemic Manifestations

Drug-induced lupus erythematosus has features distinct from primary systemic lupus erythematosus. It can occur with a wide variety of agents that result in the generation of anti-histone or other types of antibodies. Systemic manifestations of drug-induced systemic lupus erythematosus may include renal dysfunction due to circulating immune complexes or due to other immune reactions to the culprit medication(s). Acute interstitial nephritis occurs due to DNA–drug or protein–drug complexes that trigger an allergic immune response. We report a patient who developed acute kidney injury, rash, and drug-induced systemic lupus diagnosed by serologies after starting chlorthalidone and amiodarone. A renal biopsy showed acute interstitial nephritis and not lupus-induced glomerulonephritis. It is important to note that systemic lupus erythematosus and acute interstitial nephritis can occur together, and this report highlights the role of the kidney biopsy in ascertaining the pathological diagnosis and outlining therapy in drug-induced lupus erythematosus.

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P0523PROTECTIVE ROLE OF REGULATORY B CELLS ON THE RENAL TISSUE REPAIRMEN AFTER ISCHEMIA REPERCUSSION INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0523 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Yokota Yunosuke ◽

Goh Kodama ◽

Sakuya Itou ◽

Yosuke Nakayama ◽

Nobukazu Komatsu ◽

...

Keyword(s):

Flow Cytometry ◽

Renal Function ◽

B Cells ◽

Interleukin 10 ◽

Renal Tissue ◽

Protective Role ◽

Regulatory B Cells ◽

Tubulointerstitial Injury ◽

Iri Model

Abstract Background and Aims Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end- stage renal disease. It has been postulated that interleukin-10 (IL-10)-producing Regulatory B cells (Breg) play an important role for the tissue repairment in several tissues and organs. Basically, protective role of Breg has been reported in inflammatory bowel disease. In the kidney, it has been shown that IL-10 suppresses renal function decline and improves renal prognosis in IRI model, a typical model of AKI. However, the identity of Breg in the kidney and their origin have not been clarified. Further, how the Breg works during the transition from AKI to CKD is not known. Therefore, first we investigated whether Breg existed in renal tissue on the progression from AKI to CKD in IRI model mice. Further, we performed splenectomy, and examined the renal injury, Breg, and plasma IL-10 levels in this model. Method To examine the existence of Breg in the kidney of IRI model, we used 8-10 weeks-old GFP / IL-10 mice based on C57BL / 6J mice. They are reporter mice for IL-10 producing cells, and can visualize IL-10 producing cells under a fluorescence microscope without fluorescent immunostaining. We prepared following three groups, sham, IRI (unilateral), and IRI + SN (splenectomy) groups. Mice were anesthetized with chloral hydrate (4 g/kg,, intraperitoneal). After making a midline incision, exposed a blood vessel of the left renal pedicles and clamped it for 30 min by clips. one day, 7 days, and 14 days after the surgery, mice were sacrificed, and renal function and plasma IL-10 levels as well as tissue damages by PAS and Masson’s Trichrome staining were assessed. Tissue IL-10-producing cells were detected by flow cytometry. Results There was no difference of plasma IL-10 levels and renal tubulointerstitial injury in IRI group and IRI+SN group on day 1 after IRI. However, on day 7 and day 14, plasma IL-10 levels became gradually higher in IRI group, and SN decreased the increase in IL-10 levels. Tubulointerstitial injury was induced by IRI and SN further worsened tubular damages. Serum Cr and BUN levels were not different in three groups due to normal right kidney. On day 1, number of IL-10-producing B cells increased in the spleen and renal medulla in IRI group confirmed by flow cytometry, which was completely diminished by SN, suggesting that origin of the infiltrated Breg might be spleen, thereby being involved in the protective role in IRI injury in the kidney. Conclusion We report for the first time that Breg might be recruited from spleen by AKI, which may be one of the mechanisms to prevent the progression to CKD.

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Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/23247096211001659 ◽

2021 ◽

Vol 9 ◽

pp. 232470962110016

Author(s):

B. K. Anupama ◽

Parth Sampat ◽

Harvir S. Gambhir

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Case Report ◽

Interstitial Nephritis ◽

Visual Hallucination ◽

Kidney Injury ◽

Corticosteroid Administration ◽

Granulomatous Interstitial Nephritis ◽

Rare Association ◽

New Onset

We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.

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Renalase and Biomarkers of Contrast-Induced Acute Kidney Injury

Cardiorenal Medicine ◽

10.1159/000439117 ◽

2015 ◽

Vol 6 (1) ◽

pp. 25-36 ◽

Cited By ~ 10

Author(s):

Maciej T. Wybraniec ◽

Katarzyna Mizia-Stec

Keyword(s):

Acute Kidney Injury ◽

Renal Injury ◽

Amine Oxidase ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Creatinine Concentration ◽

Invasive Cardiology ◽

Proximal Tubular ◽

Novel Biomarkers

Background: Contrast-induced acute kidney injury (CI-AKI) remains one of the crucial issues related to the development of invasive cardiology. The massive use of contrast media exposes patients to a great risk of contrast-induced nephropathy and chronic kidney disease development, and increases morbidity and mortality rates. The serum creatinine concentration does not allow for a timely and accurate CI-AKI diagnosis; hence numerous other biomarkers of renal injury have been proposed. Renalase, a novel catecholamine-metabolizing amine oxidase, is synthesized mainly in proximal tubular cells and secreted into urine and blood. It is primarily engaged in the degradation of circulating catecholamines. Notwithstanding its key role in blood pressure regulation, renalase remains a potential CI-AKI biomarker, which was shown to be markedly downregulated in the aftermath of renal injury. In this sense, renalase appears to be the first CI-AKI marker revealing an actual loss of renal function and indicating disease severity. Summary: The purpose of this review is to summarize the contemporary knowledge about the application of novel biomarkers of CI-AKI and to highlight the potential role of renalase as a functional marker of contrast-induced renal injury. Key Messages: Renalase may constitute a missing biochemical link in the mutual interplay between kidney and cardiac pathology known as the cardiorenal syndrome.

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Impact of Cardiac Function Improvement on Cardiac Surgery Associated Acute Kidney Injury for Patients with Preoperative Renal Dysfunction

10.21203/rs.3.rs-58733/v1 ◽

2020 ◽

Author(s):

Jiarui Xu ◽

Xin Chen ◽

Jing Lin ◽

Yang Li ◽

Bo Shen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Cardiac Surgery ◽

Cardiac Function ◽

Renal Dysfunction ◽

Significant Risk ◽

Kidney Injury ◽

Normal Function ◽

Function Group ◽

Postoperative Aki

Abstract Background: We aim to investigate whether the postoperative cardiac function improve or not would affect the risk of cardiac surgery associated acute kidney injury (AKI) for patients with preoperative renal dysfunction. Method: Data from patients underwent cardiac surgery from April 2012 to February 2016 were collected. Renal dysfunction was defined as preoperative SCr >1.2 mg/dL (females) or >1.5 mg/dL (males). Patients were grouped as normal renal function group, renal dysfunction with chronic kidney disease (CKD group), and non CKD group. △LVEF=postoperative LVEF - preoperative LVEF. Cardiac function improved was defined as △LVEF ≥10. Patients were further divided into non CKD & cardiac function improved (non CKD+), non CKD & cardiac function not improved (non CKD-), CKD & cardiac function improved (CKD+) and CKD & cardiac function not improved (CKD-) subgroups.Results: A total of 8,661 patients were allocated as normal renal function (n=7,903), non CKD(n = 662) and CKD (n = 136) groups. Both non CKD and CKD groups had higher AKI incidence than normal function group (39.5% vs 30.0%, P < 0.001; 61.8% vs 30.0%, P<0.001), and non CKD+ group had the similar AKI incidence with normal function group (30.9% vs 30.0%, P=0.729). Multivariate logistic regression analysis revealed that non CKD-, CKD+ and CKD- were significant risk factors, whereas non CKD+ was not a significant risk factor for postoperative AKI. The SCr at discharge in non CKD+ subgroup was significantly lower than its preoperative SCr (1.4 ± 0.8 vs 1.7 ± 0.9 mg/dL, P = 0.020).Conclusions: For renal dysfunction patients with no CKD, the risk of postoperative AKI did not exist if the cardiac function improved after surgery. For CKD patients, the risk of postoperative AKI increase regardless whether the cardiac function improved or not.

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Autophagy Function and Regulation in Kidney Disease

Biomolecules ◽

10.3390/biom10010100 ◽

2020 ◽

Vol 10 (1) ◽

pp. 100 ◽

Cited By ~ 5

Author(s):

Gur P. Kaushal ◽

Kiran Chandrashekar ◽

Luis A. Juncos ◽

Sudhir V. Shah

Keyword(s):

Cell Death ◽

Renal Injury ◽

Mammalian Target Of Rapamycin ◽

Kidney Injury ◽

Therapeutic Approaches ◽

Regulated Necrosis ◽

Atg Genes ◽

Cellular Components ◽

The Impact

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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1543. Ceftaroline Model-based Dose Individualization in an Infant with Kidney Disease and Mediastinitis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1407 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S563-S563

Author(s):

Mark Murphy ◽

Sonya Tang-Girdwood ◽

Peter Tang ◽

Brady C Rebecca ◽

Tomoyuki Mizuno ◽

...

Keyword(s):

Renal Function ◽

Kidney Disease ◽

Renal Dysfunction ◽

Drug Exposure ◽

Kidney Injury ◽

Dosing Regimen ◽

Dose Individualization ◽

Model Based ◽

First Case ◽

High Concentrations

Abstract Background Options for the treatment of infections caused by resistant gram-positive bacteria are limited in children with kidney disease. Ceftaroline (CFD) may be an attractive option but dosing recommendations are not available for children with renal dysfunction. We present a case of pharmacokinetics (PK) model-based individualization of CFD in an infant with kidney disease and mediastinitis. A 5-week-old infant with a hypoplastic left side of the heart developed mediastinitis following a Norwood and BT shunt. Blood and chest washout cultures grew S. epidermidis. Vancomycin therapy led to acute kidney injury (AKI) (eGFR ~15mL/minute) and therefore, CFD was initiated at 8 mg/kg every 12 hours. The model-based clinical service was consulted to assist with dosing. Methods Plasma levels were drawn on day 2 and 10 of CFD. CFD concentrations were determined by HPLC. The pharmacodynamic (PD) target used the MIC of the isolate, 1 µg/mL, and assumed drug diffusion into the mediastinum at 20% of plasma. The PD target was ƒT>MIC at 100%. Individual PK parameters were estimated using Bayesian estimation with MWPharm++ (Mediware, the Netherlands). Results CFD dosing of 8 mg/kg every 12 hours resulted in concentrations well above the target. The trough level was 10 times higher than levels seen in clinical trials. Repeat levels were checked on day 10 due to improved renal function (eGFR 30 mL/minute) and changes in volume status. Changes in both clearance and volume were noted. ƒT>MIC was maintained 100% during dosing intervals. We dose optimized CFD to achieve the target while minimizing potential toxicity with long-term use. A new dosing regimen, 5.4 mg/kg every 8 hours, was started on day 12 and continued for 6 weeks. Conclusion This is the first case report of CFD use in a child with AKI. Though initial dosing resulted in high concentrations, no adverse effects were noted. Successful treatment was completed with a final dosing regimen of 5.3 mg/kg every 8 hours, below the recommended 8 mg/kg every 8 hours. Lower dosing was needed to decrease high drug exposure due to the decreased clearance. This case also demonstrated the feasibility of PK model-based precision dosing within 48 hours, and documented utility in the setting of changes in renal function. Further PK/PD studies are needed in children with renal dysfunction. Disclosures All authors: No reported disclosures.

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Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat

AJP Renal Physiology ◽

10.1152/ajprenal.00421.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. F308-F315 ◽

Cited By ~ 38

Author(s):

Christine Maric-Bilkan ◽

Elizabeth R. Flynn ◽

Alejandro R. Chade

Keyword(s):

Renal Function ◽

Renal Injury ◽

Ex Vivo ◽

Three Dimensional ◽

Microvascular Disease ◽

Renal Tissue ◽

Diabetic Rat ◽

Sprague Dawley ◽

Micro Computed Tomography ◽

Diabetic Kidney

Diabetic nephropathy is a progressive and generalized vasculopathic condition associated with abnormal angiogenesis. We aim to determine whether changes in renal microvascular (MV) density correlate with and play a role in the progressive deterioration of renal function in diabetes. We hypothesize that MV changes represent the early steps of renal injury that worsen as diabetes progresses, initiating a vicious circle that leads to irreversible renal injury. Male nondiabetic (ND) or streptozotocin-induced diabetic (D) Sprague-Dawley rats were followed for 4 or 12 wk. Renal blood flow and glomerular filtration rate (GFR) were measured by PAH and 125I-[iothalamate], respectively. Renal MV density was quantified ex vivo using three-dimensional micro computed tomography and JG-12 immunoreactivity. Vascular endothelial growth factor (VEGF) levels (ELISA) and expression of VEGF receptors and factors involved in MV remodeling were quantified in renal tissue by Western blotting. Finally, renal morphology was investigated by histology. Four weeks of diabetes was associated with increased GFR, accompanied by a 34% reduction in renal MV density and augmented renal VEGF levels. However, at 12 wk, while GFR remained similarly elevated, reduction of MV density was more pronounced (75%) and associated with increased MV remodeling, renal fibrosis, but unchanged renal VEGF compared with ND at 12 wk. The damage, loss, and subsequent remodeling of the renal MV architecture in the diabetic kidney may represent the initiating events of progressive renal injury. This study suggests a novel concept of MV disease as an early instigator of diabetic kidney disease that may precede and likely promote the decline in renal function.

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Use of Pamidronate for Hypercalcemia of Malignancy in Renal Dysfunction

Journal of Pharmacy Practice ◽

10.1177/0897190019883162 ◽

2019 ◽

pp. 089719001988316 ◽

Cited By ~ 1

Author(s):

Sarah J. Norman ◽

David J. Reeves ◽

Lindsay M. Saum

Keyword(s):

Renal Function ◽

Renal Dysfunction ◽

Chart Review ◽

Kidney Injury ◽

Retrospective Chart Review ◽

Primary Objective ◽

Limited Impact ◽

Hypercalcemia Of Malignancy ◽

Baseline Renal Function ◽

Community Teaching

Background: Few studies have been conducted investigating the use of bisphosphonates in hypercalcemia of malignancy (HCM) in the setting of renal dysfunction. Objective: The primary objective was to compare the incidence of acute kidney injury (AKI) within 7 days of receiving pamidronate for the treatment of HCM with pre-existing renal dysfunction versus normal renal function at the time of pamidronate administration. The secondary objectives explored the effects of pamidronate doses and infusion rates on the safety and efficacy in those with pre-existing renal dysfunction for the treatment of HCM. Methods: A retrospective chart review was conducted on patients who received pamidronate for the treatment of HCM at a community teaching hospital in Indianapolis, Indiana, from January 1, 2013, to May 31, 2017. Results: A total of 141 pamidronate administrations were included (116 patients had normal baseline renal function, and 25 patients had pre-existing renal dysfunction before pamidronate administration for the treatment of HCM). Two (8%) patients developed AKI in the pre-existing renal dysfunction group, compared with 4 (3.4%) patients in those without pre-existing renal dysfunction ( P = .288). For those with pre-existing renal dysfunction, the incidence of AKI did not differ based on the dosage of pamidronate given ( P = .762) or infusion rates ( P = .373). Conclusion: Pamidronate appears to have limited impact on renal function at doses up to 90 mg in the setting of pre-existing renal dysfunction for the treatment of HCM.

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