Distinct developmental reprogramming footprint of macrophages during acute kidney injury across species.

Acute kidney injury (AKI) is a common finding in hospitalized patients, particularly those who are critically ill. The development of AKI is associated with several adverse outcomes including mortality, morbidity, progression to chronic kidney disease, and an increase in healthcare expenditure. Despite the well-established negative impact of AKI and rigorous efforts to better define, identify, and implement targeted therapies, the overall approach to the treatment of AKI continues to principally encompass supportive measures. This enduring challenge is primarily due to the heterogeneous nature of insults that activate many independent and overlapping molecular pathways. Consequently, it is evident that the identification of common mechanisms that mediate the pathogenesis of AKI, independent of etiology and engaged pathophysiological pathways, is of paramount importance and could lead to the identification of novel therapeutic targets. To better distinguish the commonly modulated mechanisms of AKI, we explored the transcriptional characteristics of human kidney biopsies from patients with acute tubular necrosis (ATN), and acute interstitial nephritis (AIN) using a NanoString inflammation panel. Subsequently, we used publicly available single-cell transcriptional resources to better interpret the generated transcriptional findings. Our findings identify robust acute kidney injury (AKI-induced) developmental reprogramming of macrophages (MΦ) with the expansion of C1Q+, CD163+ MΦ that is independent of the etiology of AKI and conserved across mouse and human species. These results would expand the current understanding of the pathophysiology of AKI and potentially offer novel targets for additional studies to enhance the translational transition of AKI research.NEW & NOTEWORTHY Our findings identify robust acute kidney injury (AKI)-induced developmental reprogramming of macrophages (MΦ) with the expansion of C1Q+, CD163+ MΦ that is independent of the etiology of AKI and conserved across mouse and human species.

Daily dose of metformin caused acute kidney injury with lactic acidosis: a case report.

BACKGROUND: Metformin-induced lactic acidosis with acute kidney injury is rare but well known. Here we report a case of a Japanese patient taking metformin who experienced severe acute renal failure accompanied with significantly elevated metformin plasma concentrations and signs of lactic acidosis. CASE PRESENTATION: A 60-year-old Japanese man with type II diabetes, who was taking metformin (500 mg three times a day) along with several other medications, visited the emergency department with dizziness, malaise, and oliguria. The initial laboratory test results showed elevated levels of serum creatinine and blood urea nitrogen, although his renal function was normal approximately 2 weeks earlier. His lactate level was raised (4.27 mmol/L), and he was diagnosed with lactic acidosis. Considering the low creatinine clearance and elevated urinary albumin/serum creatinine ratio, urinary N-acetyl-ß-D-glucosaminidase level, and ß2-microglobulin level, the patient was further diagnosed with AKI (in other words, acute tubular necrosis). A renal biopsy performed on day 3 after admission revealed renal tubular epithelium necrosis, supporting this diagnosis. The patient underwent intermittent hemodialysis until he was discharged on day 13. The metformin concentrations on days 3, 5, and 7 were 8.95, 2.58, and 0.16 µg/mL, respectively, which is significantly higher than the maximal steady-state concentration of metformin at the recommended dosage (approximately 1 µg/mL). The calculated pharmacokinetic parameters of metformin suggested poor renal excretion and a low distribution volume at higher metformin levels. Other possible acute kidney injury-causing factors included dehydration, alcohol consumption, and the use of an angiotensin receptor blocker or SGLT2 inhibitor. CONCLUSIONS: This is the first reported case of acute kidney injury possibly caused by high levels of metformin with lactic acidosis in a patient treated with the recommended metformin dose. Thus, the development of metformin-induced acute kidney injury should be considered for patients with several acute kidney injury risk factors who are taking metformin.

Biopsy-proven first dose of oxaliplatin-induced acute tubular necrosis leading to end-stage renal failure: a case report.

BACKGROUND: Oxaliplatin is an anticancer therapy for pancreatic, gastric, and colorectal cancers. It is also used in patients with carcinomas of unknown primary sites. Oxaliplatin is associated with less frequent renal dysfunction than other conventional platinum-based drugs such as cisplatin. Albeit, there have been several reports of acute kidney injury with frequent use. In all cases, renal dysfunction was temporary and did not require maintenance dialysis. There have been no previous reports of irreversible renal dysfunction after a single dose of oxaliplatin. CASE PRESENTATION: Previous reports of oxaliplatin-induced renal injury occurred after patients received multiples doses. In this study, a 75-year-old male with unknown primary cancer and underlying chronic kidney disease developed acute renal failure after receiving the first dose of oxaliplatin. Suspected of having drug-induced renal failure through an immunological mechanism, the patient was treated with steroids; however, treatment was ineffective. Renal biopsy ruled out interstitial nephritis and revealed acute tubular necrosis. Renal failure was irreversible, and the patient subsequently required maintenance hemodialysis. CONCLUSIONS: We provide the first report of pathology-confirmed acute tubular necrosis after the first dose of oxaliplatin which led to irreversible renal dysfunction and maintenance dialysis.

Clarifying expression patterns by renal lesion using transcriptome analysis and vanin-1 as a potential novel biomarker for renal injury in chickens.

Bird death is often caused by renal lesions induced by chemicals. The avian kidney has a renal portal system with significant blood flow that is sensitive to many chemicals. However, early avian biomarkers for kidney injury are yet to be identified. This study aimed to identify novel renal biomarkers. Acute kidney injury (AKI) can be divided into acute interstitial nephritis (AIN) and acute tubular necrosis (ATN). A chicken model of kidney damage was created by an injection of diclofenac or cisplatin, which caused either AIN or ATN, respectively. Microarray analysis was performed to profile the gene expression patterns in the chickens with nephropathy. A gene enrichment analysis suggested that the genes related to responses to external stimuli showed expression changes in both AIN and ATN. However, hierarchical clustering analyses suggested that gene expression patterns differed between AIN and ATN, and the number of biomarkers relating to renal damage was low. To identify early biomarkers for nephropathy, we focused on genes that were induced at various levels of renal damage. The gene, vanin-1 (VNN1) was highly induced in the early stages of renal damage. A quantitative real-time PCR analysis supported this finding. These results suggest VNN1 could be a useful early biomarker of kidney injury in avian species.

The Proximal Tubule as the Pathogenic and Therapeutic Target in Acute Kidney Injury.

BACKGROUND: In 2004, the term acute kidney injury (AKI) was introduced with the intention of broadening our understanding of rapid declines in renal function and to replace the historical terms of acute renal failure and acute tubular necrosis (ATN). Despite this evolution in terminology, the mechanisms of AKI have stayed largely elusive with the pathophysiological concepts of ATN remaining the mainstay in our understanding of AKI. SUMMARY: The proximal tubule (PT), having the highest mitochondrial content in the kidney and relying heavily on oxidative phosphorylation to generate ATP, is vulnerable to ischaemic insults and mitochondrial dysfunction. Histologically, pathological changes in the PT are more consistent than changes to the glomeruli or the loop of Henle in AKI. Physiologically, activation of tubuloglomerular feedback due to PT dysfunction leads to an increase in preglomerular afferent arteriole resistance and a reduction in glomerular filtration. Pharmacologically, frusemide - a drug commonly used in the setting of oliguric AKI - is actively secreted by the PT and its diuretic effect is compromised by its failure to be secreted into the urine and thus be delivered to its site of action at the loop of Henle in AKI. Increases in the urinary, but not plasma biomarkers, of PT injury within 1 h of shock suggest that the PT as the initiation pathogenic target of AKI. KEY MESSAGE: Therapeutic agents targeting specifically the PT epithelial cells, in particular its mitochondria - including amino acid ergothioneine and superoxide scavenger MitoTEMPO - show great promises in ameliorating AKI.

Vitamin C Deficiency Causes Cell Type-Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model.

BACKGROUND: Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown. METHODS: We showed that vitamin C deficiency leads to acute tubular necrosis (ATN) using a vitamin C-deficient mouse model (Gulo knock-out). DNA/RNA epigenetic modifications and injured S3 proximal tubule cells were identified in the vitamin C-deficient kidneys using whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing. RESULTS: Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C-deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C-induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN. CONCLUSIONS: Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.

Monitoring intracellular tacrolimus concentrations and its relationship with rejection in the early phase after renal transplantation.

INTRODUCTION: After kidney transplantation, rejection and drug-related toxicity occur despite tacrolimus whole-blood pre-dose concentrations ([Tac]blood) being within the target range. The tacrolimus concentration within peripheral blood mononuclear cells ([Tac]cells) might correlate better with clinical outcomes. The aim of this study was to investigate the correlation between [Tac]blood and [Tac]cells, the evolution of [Tac]cells and the [Tac]cells/[Tac]blood ratio, and to assess the relationship between tacrolimus concentrations and the occurrence of rejection. METHODS: In this prospective study, samples for the measurement of [Tac]blood and [Tac]cells were collected on days 3 and 10 after kidney transplantation, and on the morning of a for-cause kidney transplant biopsy. Biopsies were reviewed according to the Banff 2019 update. RESULTS: Eighty-three [Tac]cells samples were measured of 44 kidney transplant recipients. The correlation between [Tac]cells and [Tac]blood was poor (Pearson's r = 0.56 (day 3); r = 0.20 (day 10)). Both the dose-corrected [Tac]cells and the [Tac]cells/[Tac]blood ratio were not significantly different between days 3 and 10, and the median inter-occasion variability of the dose-corrected [Tac]cells and the [Tac]cells/[Tac]blood ratio were 19.4% and 23.4%, respectively (n = 24). Neither [Tac]cells, [Tac]blood, nor the [Tac]cells/[Tac]blood ratio were significantly different between patients with biopsy-proven acute rejection (n = 4) and patients with acute tubular necrosis (n = 4) or a cancelled biopsy (n = 9; p > 0.05). CONCLUSION: Tacrolimus exposure and distribution appeared stable in the early phase after transplantation. [Tac]cells was not significantly associated with the occurrence of rejection. A possible explanation for these results might be related to the low number of patients included in this study and also due to the fact that PBMCs are not a specific enough matrix to monitor tacrolimus concentrations.

Reversed diastolic flow in a renal transplant due to ureteric obstruction from intraluminal blood clot.

Reversal of arterial diastolic flow is commonly considered a sign of transplant renal vein thrombosis until proven otherwise, with the differential including acute rejection, acute tubular necrosis, and perirenal hematoma. We discuss a case of a patient who presented with decreased urine output on the second postoperative day following living unrelated kidney transplantation. Doppler ultrasound was performed and demonstrated reversal of diastolic flow in the transplant renal artery. Prompt surgical exploration revealed intraluminal blood clot obstructing the ureter. To our knowledge, this is the first reported case of reversed diastolic flow secondary to ureteral obstruction by an intraluminal blood clot.

Pathological Features of Recovery or Progression in Acute Tubular Necrosis: Single Centre Study.

Acute tubular necrosis (ATN) is the most important and frequent cause of acute kidney injury (AKI). Controversy exists concerning the role of renal biopsy in the evaluation of ATN prognosis. We aim in our study to evaluate the role of renal biopsy for the detection of recovery and progression and rate of recovery of ATN. The study was designed to include all biopsies with the diagnosis in ATN in adults >21-year-old, from January 2016 to December 2018. Biopsies were recruited retrospectively and were reviewed by three pathologists and quantitated. Four histological ATN features were evaluated. Flattening cells, distension or dilatation, debris, and vacuolation and for each a score were attributed as follows: 0 = less than 5% of section, 1 = 6%-25%, 2 = 26%-50%, 3 = >50%. Thirty-five patients with 35 renal biopsies were analyzed. Flattening was seen <5% in nine patients, 6%-25% in 15 patients, 26%-50% in six patients. and >50% in five patients. Dilatation was seen <5% in 11 patient, 6%-25% in 10 patients, 26%-50% seen in six patients, and >50% in eight patients. The presence of debris was seen in <5% in 12 patients, 6%-25% in 12 patients, 26%-50% seen in six patients, and >50% seen in five patient. Vacuolation was seen in 5% in eight patients, 6%-25% in 14 patients, 26%-50% in seven patients, and >50% in six patients. It was found that flattening <5% and dilatation <5% and dilatation >50% in renal biopsy are the good indicators for recovery and good prognosis of cases of ATN, in addition debris <5% and >50% and vacuolation <5% are also good indicators for recovery and good prognosis of cases of ATN. On the other hand, flattening from 6% to 25% and from 26% to 50%, dilatation from 6% to 25%, debris from 26% to 50% and vacuolation >50% are also indicators for delayed recovery and poor prognosis of cases of ATN. Renal biopsy in AKI with the diagnosis of ATN with scoring system of flattening, dilatation, debris, and vacuolation can point to indication of recovery or progression of these cases.

[Kidney damage in COVID-19]. / Les atteintes rénales de la COVID-19.

COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.

Renal Considerations in COVID-19: Biology, Pathology, and Pathophysiology.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.

Urinary NGAL as a Diagnostic and Prognostic Marker for Acute Kidney Injury in Cirrhosis: A Prospective Study.

INTRODUCTION: Urinary neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in differentiating acute tubular necrosis (ATN) from other types of acute kidney injuries (AKIs) in cirrhosis, particularly hepatorenal syndrome (HRS). However, NGAL is not currently available in clinical practice in North America. METHODS: Urinary NGAL was measured in a prospective cohort of 213 US hospitalized patients with decompensated cirrhosis (161 with AKI and 52 reference patients without AKI). NGAL was assessed for its ability to discriminate ATN from non-ATN AKI and to predict 90-day outcomes. RESULTS: Among patients with AKI, 57 (35%) had prerenal AKI, 55 (34%) had HRS, and 49 (30%) had ATN, with a median serum creatinine of 2.0 (interquartile range 1.5, 3.0) mg/dL at enrollment. At an optimal cutpoint of 244 µg/g creatinine, NGAL distinguished ATN (344 [132, 1,429] µg/g creatinine) from prerenal AKI (45 [0, 154] µg/g) or HRS (110 [50, 393] µg/g; P < 0.001), with a C statistic of 0.762 (95% confidence interval 0.682, 0.842). By 90 days, 71 of 213 patients (33%) died. Higher median NGAL was associated with death (159 [50, 865] vs 58 [0, 191] µg/g; P < 0.001). In adjusted and unadjusted analysis, NGAL significantly predicted 90-day transplant-free survival (P < 0.05 for all Cox models) and outperformed Model for End-Stage Liver Disease score by C statistic (0.697 vs 0.686; P = 0.04), net reclassification index (37%; P = 0.008), and integrated discrimination increment (2.7%; P = 0.02). DISCUSSION: NGAL differentiates the type of AKI in cirrhosis and may improve prediction of mortality; therefore, it holds potential to affect management of AKI in cirrhosis.

The Role of Renal Pathology in the Prognosis and Recovery of Community-Acquired Acute Kidney Injury.

OBJECTIVES: The determinants leading to different renal outcomes in community-acquired acute kidney injury (CA-AKI) and the influence of renal histological damage on the prognosis and recovery of CA-AKI are scarcely reported. METHODS: Adult patients with CA-AKI admitted to Shanghai Changzheng Hospital with renal biopsy profiles from January 1, 2010, to December 31, 2018, were enrolled in our cohort. After 3 months of follow-up, clinical outcomes, including patient survival, dialysis requirement during hospitalization and at 3 months, CKD stage 3-5, and renal functional recovery at 3 months, were analyzed, and risk factors were identified. RESULTS: A total of 294 patients with CA-AKI with renal pathology were identified for this cohort. Among 282 patients who survived 3 months after AKI, 59.6% completely recovered, 21.3% partially recovered, 21.3% progressed to stage 3-5 CKD without dialysis, and 17.7% maintained dialysis. Moreover, 70.4% of patients in the cohort presented with de novo intrinsic renal disease, except acute tubular necrosis or acute interstitial nephritis, on renal biopsy. In the multivariate analyses, clinical factors were more related to short-term outcomes and severity of CA-AKI, represented by mortality, in-hospital dialysis, and CRRT requirement, while pathological elements were more involved with CKD progression, including dialysis-dependent or stage 3-5 CKD, and renal function recovery at the 3-month follow-up. The detrimental influence of glomerular and arterial lesions on renal prognosis of CA-AKI was as critical as tubular and interstitial lesions. CONCLUSIONS: Clinical and pathological parameters both contribute to patient and renal outcomes after CA-AKI. The value of renal biopsy should be recognized in prognostic prediction.

Renal hemosiderosis presenting with acute kidney Injury and macroscopic hematuria in Immunoglobulin A nephropathy: a case report.

BACKGROUND: Macroscopic hematuria-associated acute kidney injury (AKI) is a well-known complication of immunoglobulin A (IgA) nephropathy. In such cases, intratubular obstruction by red blood cell (RBC) casts and acute tubular necrosis are mainly observed pathologically. Herein, we report the case of a patient with IgA nephropathy presenting with AKI following an episode of macrohematuria. The patient presented with severe renal tubular hemosiderosis and acute tubular necrosis and without any obvious obstructive RBC casts. CASE PRESENTATION: A 68-year-old woman, who was diagnosed with IgA nephropathy on renal biopsy 6 years ago, was admitted to our hospital after an episode of macroscopic glomerular hematuria and AKI following upper respiratory tract infection. Renal biopsy showed mesangial proliferation of the glomeruli, including crescent formation in 17 % of the glomeruli, and acute tubular necrosis without obvious hemorrhage or obstructive RBC casts. The application of Perls' Prussian blue stain showed hemosiderin deposition in the renal proximal tubular cells. Immunofluorescence showed granular mesangial deposits of IgA and C3. Based on these findings, she was diagnosed with acute tubular necrosis with a concurrent IgA nephropathy flare-up. Moreover, direct tubular injury by heme and iron was considered to be the cause of AKI. She was treated with intravenous pulse methylprednisolone followed by oral prednisolone. Thereafter, the gross hematuria gradually faded, and her serum creatinine levels decreased. CONCLUSIONS: IgA nephropathy presenting with acute kidney injury accompanied by macrohematuria may cause renal hemosiderosis and acute tubular necrosis without obstructive RBC casts. Hemosiderosis may be a useful indicator for determining the pathophysiology of macroscopic hematuria-associated AKI. However, renal hemosiderosis may remain undiagnosed. Thus, Perls' Prussian blue iron staining should be more widely used in patients presenting with hematuria.

Atypical hemolytic uremic syndrome and acute tubular necrosis induced by complement factor B gene (CFB) mutation: A case report.

RATIONALE: Atypical hemolytic uremic syndrome (aHUS) is an uncommon and serious disease that manifests hemolytic anemia, thrombocytopenia, and acute kidney injury. Genetic complement abnormalities have been shown to be responsible. Compared with the aHUS caused by other mutated genes, aHUS secondary to CFB mutation in adults is extremely rare. We report an adult with CFB mutation developing aHUS. PATIENT CONCERNS: A 56-year-old man was admitted for 4-day history of nausea and fatigue, anuria for 2 days, and unconsciousness for 10 hours. DIAGNOSES: The patient presented with life-threatening anemia, thrombocytopenia, acute kidney injury, and nervous system abnormalities. The patient had schistocytes on the peripheral blood smear, increased lactate dehydrogenase (LDH), and plasma-free hemoglobin levels. The patient was later found to harbor a pathogenic variant in the CFB gene (C.1598A>G), and was diagnosed with aHUS and acute kidney injury. INTERVENTION: The patient was treated by plasmapheresis, continuous renal replacement therapy, blood transfusion, and anti-infective and antihypertensive treatment. OUTCOMES: After the treatment, the patient's consciousness returned to normal, and the hemoglobin, platelet, and serum creatinine recovered. The disease activity remained quiescent during the follow-up. LESSONS: A rare heterozygous variant c.1598A>G p.Lys 533Arg in the CFB gene, which was associated with adult-onset aHUS, was described and successfully treated. This case can help in understanding the early diagnosis and effective therapies of this rare disease.

Outcomes of Delayed Graft Function in Kidney Transplant Recipients Stratified by Histologic Biopsy Findings.

Delayed graft function (DGF) after kidney transplantation is associated with an increased risk of graft failure. We studied the histologic findings among adult kidney transplant recipients transplanted between January 2000 and June 2015 who had DGF and had a kidney biopsy within 14 days of transplant. Death censored graft failure (DCGF) and death at 1 and 3 years after transplant were examined. A total of 269 transplant recipients fulfilled our selection criteria, of which 152 (56.51%) had acute tubular necrosis (ATN), 44 (16.4%) had acute rejection (AR), mainly T-cell mediated rejection (n = 31), 35 (13%) had ATN with AR (mainly T-cell mediated rejection, n = 26), and 38 (14.1%) had other pathology. Compared with those with ATN alone, kidney transplant recipients with AR alone had a significantly higher risk of DCGF at 1 year post transplant (adjusted hazard ratio = 3.70; 95% confidence interval 1.5-9.5; P = .006). Those with AR alone had an increased risk of DCGF at 3 years post transplant (hazard ratio = 3.10; 95% confidence interval 1.3-8.5; P = .01) in crude analyses. There was no association between DGF etiology and mortality. Early renal biopsy can be used to distinguish AR, which has protocolized treatments, from other etiologies. This could potentially alter allograft survival within 1 year of transplant complicated by DGF.

Lansoprazole promotes cisplatin-induced acute kidney injury via enhancing tubular necroptosis.

Acute kidney injury (AKI) is the main obstacle that limits the use of cisplatin in cancer treatment. Proton pump inhibitors (PPIs), the most commonly used class of medications for gastrointestinal complications in cancer patients, have been reported to cause adverse renal events. However, the effect of PPIs on cisplatin-induced AKI remains unclear. Herein, the effect and mechanism of lansoprazole (LPZ), one of the most frequently prescribed PPIs, on cisplatin-induced AKI were investigated in vivo and in vitro. C57BL/6 mice received a single intraperitoneal (i.p.) injection of cisplatin (18 mg/kg) to induce AKI, and LPZ (12.5 or 25 mg/kg) was administered 2 hours prior to cisplatin administration and then once daily for another 2 days via i.p. injection. The results showed that LPZ significantly aggravated the tubular damage and further increased the elevated levels of serum creatinine and blood urea nitrogen induced by cisplatin. However, LPZ did not enhance cisplatin-induced tubular apoptosis, as evidenced by a lack of significant change in mRNA and protein expression of Bax/Bcl-2 ratio and TUNEL staining. Notably, LPZ increased the number of necrotic renal tubular cells compared to that by cisplatin treatment alone, which was further confirmed by the elevated necroptosis-associated protein expression of RIPK1, p-RIPK3 and p-MLKL. Furthermore, LPZ deteriorated cisplatin-induced inflammation, as revealed by the increased mRNA expression of pro-inflammatory factors including, NLRP3, IL-1ß, TNF-α and caspase 1, as well as neutrophil infiltration. Consistently, in in vitro study, LPZ increased HK-2 cell death and enhanced inflammation, compared with cisplatin treatment alone. Collectively, our results demonstrate that LPZ aggravates cisplatin-induced AKI, and necroptosis may be involved in the exacerbation of kidney damage.