Imaging features of immune checkpoint inhibitor-related nephritis with clinical correlation: a retrospective series of biopsy-proven cases.

OBJECTIVES: Imaging appearances of immune checkpoint inhibitor-related nephritis have not yet been described. The primary objective of this study is to describe the appearances of immunotherapy-related nephritis on computerized tomography (CT) and positron emission tomography (PET). The secondary objectives are to investigate the association of radiologic features with clinical outcomes. METHODS: CT and PET-CT scans before the initiation of immunotherapy (baseline), at nephritis, and after resolution of pathology-proven nephritis cases were reviewed. Total kidney volume, renal parenchymal SUVmax, renal pelvis SUVmax, and blood pool SUVmean were obtained. RESULTS: Thirty-four patients were included. The total kidney volume was significantly higher at nephritis compared to baseline (464.7 ± 96.8 mL vs. 371.7 ± 187.7 mL; p < 0.001). Fifteen patients (44.1%) had > 30% increase in total kidney volume, which was associated with significantly higher renal toxicity grade (p = 0.007), higher peak creatinine level (p = 0.004), and more aggressive medical treatment (p = 0.011). New/increasing perinephric fat stranding was noted in 10 patients (29.4%) at nephritis. Among 8 patients with contrast-enhanced CT at nephritis, one (12.5%) developed bilateral wedge-shaped hypoenhancing cortical. On PET-CT, the renal parenchymal SUVmax-to-blood pool ratio was significantly higher at nephritis compared to baseline (2.13 vs. 1.68; p = 0.035). The renal pelvis SUVmax-to-blood pool SUVmean ratio was significantly lower at nephritis compared to baseline (3.47 vs. 8.22; p = 0.011). CONCLUSIONS: Bilateral increase in kidney size, new/increasing perinephric stranding, and bilateral wedge-shaped hypoenhancing cortical foci can occur in immunotherapy-related nephritis. On PET-CT, a diffuse increase in radiotracer uptake throughout the renal cortex and a decrease in radiotracer activity in the renal pelvis can be seen. KEY POINTS: • CT features of immune checkpoint inhibitor-related nephritis include an increase in kidney volume, new/increasing perinephric stranding, and bilateral ill-defined wedge-shaped hypoenhancing cortical foci. • FDG-PET features of immune checkpoint inhibitor-related nephritis include an increase in FDG uptake throughout the renal cortex and a decrease in FDG activity/excretion in the collecting system. • > 30% increase in total kidney volume is associated with worse toxicity grade and more aggressive medical management.

Urinary T cells are detected in patients with immune checkpoint inhibitor-associated immune nephritis that are clonotypically identical to kidney T cell infiltrates.

Acute kidney injury (AKI) occurs in ~20% of patients receiving immune checkpoint inhibitor (ICI) therapy; however, only 2-5% will develop ICI-mediated immune nephritis. Conventional tests are nonspecific in diagnosing disease pathology and invasive procedures (i.e. kidney biopsy) may not be feasible. In other autoimmune renal diseases, urinary immune cells correlated with the pathology or were predictive of disease activity. Corresponding evidence and analysis are absent for ICI-mediated immune nephritis. We report the first investigation analyzing immune cell profiles of matched kidney biopsies and urine of patients with ICI-AKI. We demonstrated the presence of urinary T cells in patients with immune nephritis by flow cytometry analysis. Clonotype analysis of T cell receptor (TCR) sequences confirmed enrichment of kidney TCRs in urine. As ICI therapies become standard of care for more cancers, noninvasively assessing urinary immune cells of ICI therapy recipients can facilitate clinical management and an opportunity to tailor ICI-nephritis treatment.

Immune checkpoint inhibitor-induced refractory polyarthritis rapidly improved by sarilumab and monitoring with joint ultrasonography: A case report.

RATIONALE: Immune checkpoint inhibitors (ICIs) have shown efficacy for the treatment of various kinds of malignant tumors. However, ICIs can cause immune-related adverse events, such as arthritis. Nevertheless, the treatment of ICI-induced arthritis has not been established yet. Here we report a case of ICI-induced polyarthritis successfully treated using sarilumab and monitored using joint ultrasonography. PATIENT CONCERNS: A 61-year-old man presented with polyarthritis. He had been treated with nivolumab for recurrent renal cell carcinoma 11 months before. He developed ICI-induced nephritis (proteinuria and elevated serum creatinine) 3 months before, which resolved after discontinuing nivolumab for 1 month. Two months after resuming nivolumab, he developed polyarthralgia and joint swelling, which were suspected to be associated with nivolumab administration, and hence we discontinued nivolumab again. Laboratory tests revealed elevated C-reactive protein level and erythrocyte sedimentation rate, but were negative for rheumatoid factor and anti-cyclic citrullinated peptide antibody. Joint ultrasonography revealed active synovitis in several joints, but a joint X-ray revealed no bone erosion. DIAGNOSES: We diagnosed polyarthritis as ICI-induced arthritis because the findings were not typical of rheumatoid arthritis (no bone erosion and seronegativity) and the patient had already developed other immune-related adverse events (ICI-induced nephritis). INTERVENTIONS: After discontinuation of nivolumab, we started treatment with 15 mg daily prednisolone and 1000 mg daily sulfasalazine, although it was ineffective. Hence, we initiated 200 mg biweekly sarilumab. OUTCOMES: Following sarilumab administration, polyarthritis improved rapidly, and joint ultrasonography confirmed the rapid improvement of synovitis. Hence, we tapered off the glucocorticoid treatment. No recurrence of renal cell carcinoma was noted for 2 years after the initiation of sarilumab despite no anti-tumor therapy. LESSONS: Sarilumab may serve as a good treatment option for treating refractory ICI-induced polyarthritis. Joint ultrasonography may contribute to the evaluation of ICI-induced polyarthritis and monitoring the effects of treatments.

Nephrotoxicity of immune checkpoint inhibitor therapy: a pharmacovigilance study.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has demonstrated impressive clinical benefits across cancers. However, adverse drug reactions (ADRs) occur in every organ system, often due to autoimmune syndromes. We sought to investigate the association between ICI therapy and nephrotoxicity using a pharmacovigilance database, hypothesizing that inflammatory nephrotoxic syndromes would be reported more frequently in association with ICIs. METHODS: We analyzed VigiBase, the World Health Organization pharmacovigilance database, to identify renal ADRs (rADRs), such as nephritis, nephropathy and vascular disorders, reported in association with ICI therapy. We performed a disproportionality analysis to explore if rADRs were reported at a different rate with one of the ICI drugs compared with rADRs in the entire database, using an empirical Bayes estimator as a significance screen and defining the effect size with a reporting odds ratio (ROR). RESULTS: We found 2341 rADR for all examined ICI drugs, with a disproportionality signal solely for nephritis [ROR = 3.67, 95% confidence interval (CI) 3.34-4.04]. Examining the different drugs separately, pembrolizumab, nivolumab and ipilimumab + nivolumab combination therapy had significantly higher reporting odds of nephritis than the other ICI drugs (ROR = 4.54, 95% CI 3.81-5.4; ROR = 3.94, 95% CI 3.40-4.56; ROR 3.59, 95% CI 2.71-4.76, respectively). CONCLUSIONS: Using a pharmacovigilance method, we found increased odds of nephritis when examining rADRs associated with ICI therapy. Pembrolizumab, nivolumab and a combination of ipilimumab + nivolumab showed the highest odds. Clinicians should consider these findings and be aware of the increased risk of nephritis, especially in patients treated with pembrolizumab, when administering ICI therapy.

Catalpol Alleviates Ang II-Induced Renal Injury Through NF-κB Pathway and TGF-ß1/Smads Pathway.

ABSTRACT: Catalpol is an iridoid glycoside obtained from Rehmannia glutinosa, which in previous studies showed various pharmacological properties, including anti-inflammatory, antioxidant, antidiabetic, antitumor, and dopaminergic neurons protecting effects. Here, we examined the effect of catalpol on renal injury induced by angiotensin II (Ang II) and further to explore its latent molecular mechanisms. We used an in vivo model of Ang II-induced renal injury mice; catalpol (25, 50, and 100 mg/kg) was administered for 28 days. Mouse glomerular mesangial cells (SV40 MES 13), rat kidney interstitial fibroblasts cells (NRK-49F), and human proximal tubular epithelial cells (HK-2) were induced by Ang II (10 µM) in the presence or absence of catalpol (1, 5, and 10 µM) and incubated for 48 hours in vitro. In our study, periodic acid-Schiff and Masson staining of renal tissue showed that catalpol reduced Ang II-induced renal injury in a concentration-dependent manner. The positive expressions of collagen IV and TGF-ß1 were observed to decrease sharply after catalpol treatment. In renal tissue, the levels of pro-inflammatory cytokines tumor necrosis factor α and interleukin 6 were evidently decreased after catalpol intervention. Catalpol can relieve Ang II-induced renal injury by inactivating NF-κB and TGF-ß1/Smads signaling pathways. Therefore, catalpol may act as a potential drug to treat Ang II-induced renal injury.

Fibroblast growth factor 21 attenuates salt-sensitive hypertension-induced nephropathy through anti-inflammation and anti-oxidation mechanism.

BACKGROUND: Patients with salt-sensitive hypertension are often accompanied with severe renal damage and accelerate to end-stage renal disease, which currently lacks effective treatment. Fibroblast growth factor 21 (FGF21) has been shown to suppress nephropathy in both type 1 and type 2 diabetes mice. Here, we aimed to investigate the therapeutic effect of FGF21 in salt-sensitive hypertension-induced nephropathy. METHODS: Changes of FGF21 expression in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mice were detected. The influence of FGF21 knockout in mice on DOCA-salt-induced nephropathy were determined. Recombinant human FGF21 (rhFGF21) was intraperitoneally injected into DOCA-salt-induced nephropathy mice, and then the inflammatory factors, oxidative stress levels and kidney injury-related indicators were observed. In vitro, human renal tubular epithelial cells (HK-2) were challenged by palmitate acid (PA) with or without FGF21, and then changes in inflammation and oxidative stress indicators were tested. RESULTS: We observed significant elevation in circulating levels and renal expression of FGF21 in DOCA-salt-induced hypertensive mice. We found that deletion of FGF21 in mice aggravated DOCA-salt-induced nephropathy. Supplementation with rhFGF21 reversed DOCA-salt-induced kidney injury. Mechanically, rhFGF21 induced AMPK activation in DOCA-salt-treated mice and PA-stimulated HK-2 cells, which inhibited NF-κB-regulated inflammation and Nrf2-mediated oxidative stress and thus, is important for rhFGF21 protection against DOCA-salt-induced nephropathy. CONCLUSION: These findings indicated that rhFGF21 could be a promising pharmacological strategy for the treatment of salt-sensitive hypertension-induced nephropathy.

IRF-4 deficiency reduces inflammation and kidney fibrosis after folic acid-induced acute kidney injury.

The chronic phase following toxin-induced acute kidney injury (AKI) is characterized by robust inflammation and progressive kidney fibrosis. Interferon regulatory factor 4 (IRF-4) is a type of multifunctional transcription factor that has been deeply linked to inflammation and fibrotic diseases. However, the role of IRF-4 in kidney damage and renal fibrosis after toxin-induced AKI remain to be explored. In this work, we examined the effect of IRF-4 deficiency on inflammation and kidney fibrosis in an AKI-chronic kidney disease (CKD) transition model induced by folic acid (FA) injury. We showed that FA treatment resulted in severe acute tubular injury followed by inflammatory reaction and interstitial fibrosis in wild-type mice. A sharp elevation of IRF-4 levels was observed in FA-injured kidneys. IRF-4 knockout led to a substantial reduction of extracellular matrix (ECM) proteins deposition and inhibited myofibroblasts transformation in the kidneys of mice subjected to FA treatment. In addition, IRF-4 ablation impaired F4/80+ macrophages and CD3+ T lymphocytes infiltration into the FA-injured kidneys. Loss of IRF-4 reduced the production of inflammatory molecules such as CXCL16, IL-18, IL-6, and TGF-ß1 in the kidneys in response to FA stress. Following FA injury, the kidneys of IRF-4 knockout mice had fewer bone marrow-derived myofibroblasts than wild-type controls. Moreover, IRF-4 disruption inhibited macrophages to myofibroblasts differentiation in the kidneys in response to FA stimuli. In vitro, IL-4 stimulated expression of α-smooth muscle actin and ECM proteins and promoted M2 macrophages to myofibroblasts transition in mouse bone marrow-derived monocytes, which was abolished in the absence of IRF-4. Thus, we identified an important role of IRF-4 in the pathogenesis of progressive CKD following FA-induced AKI.

Protective Effect of Opuntia dillenii (Ker Gawl.) Haw. Seed Oil on Gentamicin-Induced Nephrotoxicity: A Biochemical and Histological Analysis.

Opuntia dillenii is a medicinal plant with frequent usage in folk medicine to treat many illnesses. The present study aims to investigate the protective effect of Opuntia dillenii seed oil against gentamicin-induced nephrotoxicity in rats. The animals (rats) were randomly divided into three groups (i) the normal control group treated only with distilled water (10 mL/kg), (ii) the gentamicin group treated with distilled water (10 mL/kg) and received an intraperitoneal injection of gentamicin (80 mg/kg), and (iii) the group treated with the Opuntia dillenii seed oil (2 mL/kg) and also received an intraperitoneal injection of gentamicin (80 mg/kg). The rats received their following treatments for 14 consecutive days orally. Serum urea, creatinine, gamma-glutamyl transferase, albumin, and electrolyte levels were quantified as the markers of acute renal and liver failure. Besides, the kidney and liver relative weight, kidney malondialdehydes, and kidney histological analysis were determined. The results have shown that daily pretreatment with Opuntia dillenii seed oil (2 mL/kg) prevented severe alterations of biochemical parameters and disruptions of kidney tissue structures. In addition, the results of the present study showed for the first time that Opuntia dillenii seed oil reduced renal toxicity in gentamicin-induced nephrotoxicity in rats. Therefore, Opuntia dillenii seed oil may represent a new therapeutic avenue to preserve and protect renal function in gentamicin-treated patients.

Administration of Lactobacillus reuteri Combined with Clostridium butyricum Attenuates Cisplatin-Induced Renal Damage by Gut Microbiota Reconstitution, Increasing Butyric Acid Production, and Suppressing Renal Inflammation.

Cisplatin-induced nephrotoxicity is associated with gut microbiota disturbance. The present study aimed to investigate whether supplementation of Lactobacillus reuteri and Clostridium butyricum (LCs) had a protective effect on cisplatin-induced nephrotoxicity through reconstruction of gut microbiota. Wistar rats were given different treatments: control, cisplatin (Cis), cisplatin + C. butyricum and L. reuteri (Cis+LCs), and C. butyricum and L. reuteri (LCs). We observed that cisplatin-treated rats supplemented with LCs exhibited significantly decreased renal inflammation (KIM-1, F4/80, and MPO), oxidative stress, fibrosis (collagen IV, fibronectin, and a-SMA), apoptosis, concentration of blood endotoxin and indoxyl sulfate, and increased fecal butyric acid production compared with those without supplementation. In addition, LCs improved the cisplatin-induced microbiome dysbiosis by maintaining a healthy gut microbiota structure and diversity; depleting Escherichia-Shigella and the Enterobacteriaceae family; and enriching probiotic Bifidobacterium, Ruminococcaceae, Ruminiclostridium_9, and Oscillibacter. Moreover, the LCs intervention alleviated the cisplatin-induced intestinal epithelial barrier impairment. This study indicated LCs probiotic serves as a mediator of the gut-kidney axis in cisplatin-induced nephrotoxicity to restore the intestinal microbiota composition, thereby suppressing uremic toxin production and enhancing butyrate production. Furthermore, the renoprotective effect of LCs is partially mediated by increasing the anti-inflammatory effects and maintaining the integrity of the intestinal barrier.

Probing the Hidden Role of Mitochondrial DNA Damage and Dysfunction in the Etiology of Aristolochic Acid Nephropathy.

Aristolochic acid nephropathy (AAN) is a unique type of progressive renal interstitial fibrotic disease caused by prolonged exposure to aristolochic acids (AAs) through AA-containing herbal medicines or AA-tainted food. Despite decades of research and affecting millions of people around the world, the pathophysiology of AAN remains incompletely understood. In this study, we tested the potential causative role of mitochondrial dysfunction in AAN development. Our findings revealed AA exposure induces an exposure concentration and duration dependent lowering of adenosine triphosphate in both cultured human kidney and liver cells, highlighting an AA exposure effect on mitochondrial energy production in the kidney and liver, which both are highly metabolically active and energy-demanding organs. Analysis with liquid chromatography-tandem mass spectrometry coupled with stable isotope dilution method detected high levels of mutagenic 8-oxo-2'-deoxyguanosine and 7-(deoxyadenosine-N6-yl)-aristolactam adduct on mitochondrial DNA isolated from AA-treated cells, unmasking a potentially important causative, but previously unknown role of mitochondrial DNA mutation in the pathophysiology of AAN development.

p66Shc-mediated hydrogen peroxide production impairs nephrogenesis causing reduction of number of glomeruli.

AIMS: Adaptor protein p66Shc, encoded by Shc1 gene, contributes to the pathogenesis of oxidative stress-related diseases. p66Shc ability to promote oxidative stress-related diseases requires phosphorylation of serine 36 residue (Ser36) and depends on translocation of p66Shc to the mitochondria. We tested the hypothesis that abnormal p66Shc-mediated reactive oxygen species (ROS) production could be critically involved in nephrons development during nephrogenesis. MAIN METHODS: We have generated unique mutant rats (termed p66Shc-Del), which express endogenous p66Shc with a 9-amino acid deletion, and lack regulatory Ser36. H2O2 renal production was measured by enzymatic microelectrode biosensors. Nephron numbers in 3-5 weeks old p66Shc-Del rats were quantified using the acid maceration method. KEY FINDINGS: p66Shc-Del rats, as wild type salt sensitive rats, display increased mean arterial blood pressure following chronic exposure to a high salt diet. In contrast to wild type rats, p66Shc-Del rats display increased H2O2 renal production and are characterized by a reduction in renal function. The number of glomeruli is significantly reduced in adult p66Shc-Del rats. SIGNIFICANCE: Since low nephron number is an established risk factor for kidney disease and hypertension in humans and rodents, our data suggest that H2O2 renal production, caused by irregular signaling of p66Shc, could be critical in regulating nephrogenesis and that abnormal p66Shc signaling negatively impacts kidney development and renal function by increasing susceptibility to diabetic nephropathy and hypertension-induced nephropathy.

Rapid corticosteroid taper versus standard of care for immune checkpoint inhibitor induced nephritis: a single-center retrospective cohort study.

BACKGROUND: Current guidelines for treatment of immune checkpoint inhibitor (ICI)-induced nephritis are not evidence based and may lead to excess corticosteroid exposure. We aimed to compare a rapid corticosteroid taper to standard of care. METHODS: Retrospective cohort study in patients with ICI-induced nephritis comparing a rapid taper beginning with 60 mg/day prednisone and tapered to 10 mg within 3 weeks to a historical control group that began 60 mg/day tapered to 10 mg within 6 weeks (standard of care). Renal recovery was defined as creatinine returning to within 1.5-fold baseline. The log-rank test compared the differences in time to renal recovery between the groups. We report rates of renal recovery at 30, 60 and 90 days, and timing and outcomes of ICI rechallenge. RESULTS: Thirteen patients received rapid corticosteroid taper and 14 patients received standard of care. Baseline characteristics were similar between groups. The median time to ≤10 mg/day prednisone was 20 days (IQR 15-25) in the rapid-taper group compared with 38 days (IQR 30-58) in the standard-of-care group. There was no significant difference in the time to renal recovery between the groups, though numerically higher numbers of patients recovered by 30 days, 11 (85%) in the rapid-taper arm versus 6 (46%) in the standard of care arm. Exposure to other nephritis-causing medications (proton pump inhibitor or trimethoprim-sulfamethoxazole) during the corticosteroid taper was more common in the standard of care group, 9 (64%) versus rapid-taper group, 2 (15%), and was associated with longer time to renal recovery, 20 days (IQR 14-101) versus 13 days (IQR 7-34) in those that discontinued nephritis-causing medications. Fifteen (56%) of patients were rechallenged with ICIs, and only two (13%) developed recurrent nephritis. CONCLUSIONS: Patients with ICI-induced nephritis have excellent kidney outcomes when treated with corticosteroids that are tapered over 3 weeks.

Safe anti-programmed cell death-1 rechallenge with antibody switching after immune-related adverse events: brief communication.

Aim: To evaluate the safety of rechallenge with a different anti-PD-1 antibody after an immune-related adverse event (irAE) that has prompted the discontinuation of anti-PD-1 therapy. Patients & methods: We describe two patients with metastatic melanoma who developed potentially disabling and early irAEs following anti-PD-1 treatment. Therapy was discontinued and toxicities resolved with corticosteroids. Results: Rechallenge switching to an alternative anti-PD-1 antibody did not lead to a new or recurrent irAE. Conclusion: Switching to a different anti-PD-1 antibody when resuming therapy after an irAE might be a safe strategy and warrants further investigation. Structural and biological differences between antibodies might explain the different safety outcomes.

Nephrotoxicity from Vancomycin Combined with Piperacillin-Tazobactam: A Comprehensive Review.

BACKGROUND: Recent studies have identified the combination of vancomycin with piperacillin-tazobactam (VPT) to be associated with increased nephrotoxicity. Multiple, large cohort studies have found this widely used combination to have a higher risk of nephrotoxicity than other regimens in a variety of populations. SUMMARY: This review summarizes the epidemiology and clinical features of VPT-associated acute kidney injury (AKI). Potential mechanisms involved in the pathogenesis of this phenomenon are also discussed. Key Message: VPT-associated nephrotoxicity is a recently recognized clinical entity. Clinical strategies to minimize the risk of toxicity in this setting include antimicrobial stewardship, monitoring of kidney function, and emerging data supporting the potential role for novel biomarkers in predicting and managing AKI.

High salt aggravates renal inflammation via promoting pro-inflammatory macrophage in 5/6-nephrectomized rat.

The increasing incident of chronic kidney disease (CKD) in recent years might be related to a change in dietary habits, known as excessive salt intake. Given excessive salt promotes pathogenic T cells responses. Since the importance of macrophage in the development of CKD, we addressed the effect of high salt loading on in a rat CKD model. We observed that 5/6Nx rats receiving a high salt diet showed strongly enhanced macrophage infiltration and activation in the renal tissue accompanied by deteriorated renal inflammation. Then we used the microarray expression profiling to detect the effect of additional Nacl on peritoneal macrophage derived from 5/6Nx. The NaCl treatment of macrophage extracted from 5/6Nx rat elicited a strong pro-inflammatory phenotype characterized by enhanced proinflammatory cytokine production, increased expression of molecules mainly involved in immune response process. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased phosphorylation of STAT1. Taken together, our study demonstrated that high salt intake promotes immune activation of macrophages through the STAT1 independently and exacerbates the kidney accompanied by promotion of inflammation. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of CKD.

Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury.

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. SIGNIFICANCE: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/713/F1.large.jpg.

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKß.

Cisplatin, a widely used chemotherapy for the treatment of various tumors, is clinically limited due to its extensive nephrotoxicity. Inflammatory response in tubular cells is a driving force for cisplatin-induced nephrotoxicity. The plant-derived agents are widely used to relieve cisplatin-induced renal dysfunction in preclinical studies. Polysulfide and hydrogen sulfide (H2S) are ubiquitously expressed in garlic, and both of them are documented as potential agents for preventing and treating inflammatory disorders. This study was designed to determine whether polysulfide and H2S could attenuate cisplatin nephrotoxicity through suppression of inflammatory factors. In renal proximal tubular cells, we found that sodium tetrasulfide (Na2S4), a polysulfide donor, and sodium hydrosulfide (NaHS) and GYY4137, two H2S donors, ameliorated cisplatin-caused renal toxicity through suppression of the massive production of inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Mechanistically, the anti-inflammatory actions of Na2S4 and H2S may be mediated by persulfidation of signal transducer and activator of transcription 3 (STAT3) and inhibitor kappa B kinase ß (IKKß), followed by decreased phosphorylation of STAT3 and IKKß. Moreover, the nuclear translocation of nuclear transcription factor kappa B (NF-κB), and phosphorylation and degradation of nuclear factor kappa B inhibitor protein alpha (IκBα) induced by cisplatin, were also mitigated by both polysulfide and H2S. In mice, after treatment with polysulfide and H2S donors, cisplatin-associated renal dysfunction was strikingly ameliorated, as evidenced by measurement of serum blood urea nitrogen (BUN) and creatinine levels, renal morphology, and the expression of renal inflammatory factors. Our present work suggests that polysulfide and H2S could afford protection against cisplatin nephrotoxicity, possibly via persulfidating STAT3 and IKKß and inhibiting NF-κB-mediated inflammatory cascade. Our results might shed light on the potential benefits of garlic-derived polysulfide and H2S in chemotherapy-induced renal damage.

Ergosterol ameliorates renal inflammatory responses in mice model of diabetic nephropathy.

Ergosterol (ERG) was reported to exhibit anti-inflammatory and anti-oxidative activities. Besides, ERG was found to attenuate kidney injury in the diabetic mouse. However, the protective effect of ERG in diabetic nephropathy-induced inflammation remains unclear. We aimed to study whether ERG could alleviate diabetic nephropathy-induced inflammation and explore the underlying mechanisms. The diabetic nephropathy mice model was induced by intraperitoneal injection of 30 mg/kg Streptozotocin (STZ). The inflammatory cytokines levels, and insulin concentration in the serum of both diabetic nephropathy patients and mouse model were determined by ELISA. mRNA and protein expression were analyzed by RT-PCR and Western blot, respectively. Fasting blood glucose levels were detected using a commercial kit. Blood biochemistry levels were determined by an automatic analyzer. Mesangium proliferation was detected by PAS staining. It was found that serum levels of IL-6, TNF-α, and MCP-1 dramatically increased in the diabetic nephropathy patients. In mice, ERG treatment greatly decreased fasting blood glucose levels, inflammatory cytokine levels, and renal injury, while it enhanced the insulin level. Mechanically, ERG treatment dramatically decreased NF-κB signaling pathway. Our findings highlight the potential of ERG as an effective agent to treat diabetic nephropathy.

Renal Toxicity.

With the increasing use of immunotherapy, there has been an associated increased survival in many cancers but has also resulted in unregulated organ-specific toxicities. In this chapter, we discuss the renal toxicities associated with a checkpoint inhibitor (CPI) from the typical acute tubulointersitial nephritis to glomerulonephritis, their proposed mechanisms, and treatments. We also discuss the use of CPI and reactivation of preexisting auto-immune diseases and focus on renal cell cancer in setting of Chronic kidney disease (CKD). Transplant rejection in the setting of CPI use is yet to be further studied, and available data is presented in this chapter.