Subchronic intranasal lipopolysaccharide exposure induces pulmonary autoimmunity and glomerulonephritis in NZBWF1 mice.

Lupus, a systemic autoimmune disease shaped by gene-environment interplay, often progresses to endstage renal failure. While subchronic systemic exposure to bacterial lipopolysaccharide (LPS) triggers autoimmunity and glomerulonephritis in lupus-prone mice, it is unknown if inhaling LPS, which is common in certain occupations, can similarly trigger lupus. Here we determined how subchronic intranasal (IN) LPS instillation influences autoimmunity and glomerulonephritis development in lupusprone NZBWF1 female mice. Briefly, mice were IN-instilled with vehicle or E. coli LPS (0.8 µg/g) twice weekly for 5 wk, followed by necropsy. For systemic comparison, additional cohorts of mice were injected with LPS intraperitoneally (IP) using identical doses/timing. Lungs were assessed for inflammatory and autoimmune responses and then related to systemic autoimmunity and glomerulonephritis. IN/LPS exposure induced in the lung: i) leukocyte infiltration, ii)mRNA signatures for cytokines, chemokines, IFN-regulated, and cell death-related genes, iii) ectopic lymphoid tissue formation, and iv)diverse IgM and IgG autoantibodies (AAbs). Pulmonary effects coincided with enlarged spleens, elevated plasma IgG AAbs, and inflamed IgG-containing kidney glomeruli. In contrast, IP/LPS treatment induced systemic autoimmunity and glomerulonephritis without pulmonary manifestations. Taken together, these preclinical findings suggest the lung could serve as a critical nexus for triggering autoimmunity by respirable LPS in genetically predisposed individuals.

The Unusual Adverse Effects of Antituberculosis Therapy in Kidney Patients.

BACKGROUND: Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease increases the risk of TB due to diminished glomerular filtration rate, proteinuria, and immunosuppression use. Further, the first-line anti-TB drugs are associated with acute kidney injury (AKI) even in patients with normal kidney functions. METHODS: We retrospectively identified 10 patients hospitalized with unusual adverse effects of antituberculosis therapy (ATT) from 2013 to 2022. RESULTS: We found three cases of AKI caused by rifampicin: acute interstitial nephritis, crescentic glomerulonephritis, and heme pigment-induced acute tubular necrosis. We observed rifampicin-induced accelerated hypertension and thrombocytopenia in two patients on maintenance hemodialysis. Isoniazid caused pancreatitis and cerebellitis in two CKD patients, respectively. In a CKD patient, we detected acute gout secondary to pyrazinamide-induced reduced uric acid excretion. We also observed cases of drug rash with eosinophilia and systemic symptoms and hypercalcemia due to immune reconstitution inflammatory syndrome in patients with glomerular disease on ATT. Immediate discontinuation of the offending drug, along with specific and supportive management, led to a recovery in all cases. CONCLUSION: The adverse effects of ATT may be unusually severe and varied in kidney patients due to decreased renal elimination. Early recognition of these adverse effects and timely discontinuation of the offending drug is essential to limit morbidity and mortality.

Tanshinone IIA Liposomes Treat Doxorubicin-Induced Glomerulonephritis by Modulating the Microenvironment of Fibrotic Kidneys.

Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-ß1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-ß1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.

Hydralazine use can be associated with IgM-dominated immune complex-mediated glomerulonephritis.

CONTEXT: IgM-dominant immune complex-mediated glomerulonephritis (IgM-dominant ICMGN) is a rare renal entity, characterized by a membranoproliferative pattern by light microscopy, dominant IgM staining by immunofluorescent staining, and subendothelial deposits by electron microscopy. This study was to investigate if some of IgM-ICMGN were associated with autoimmune disorders induced by hydralazine. DESIGN: Seven IgM-dominant ICMGN cases were identified over 8 years. Their pathologic phenotypes and clinical scenarios were analyzed in detail. RESULTS: Patients' ages ranged from 47 to 87 years old with 5 women and two men. Six of seven patients had drug-induced autoimmune phenomenon (hydralazine-induced positive ANCA and ANA). All of them had renal dysfunction and some proteinuria. Most pathologic features showed a membranoproliferative pattern of glomerulonephritis with dominant IgM deposits at subendothelial spaces. IgM nephropathy (a variant of focal segmental glomerulosclerosis), chronic thrombotic microangiopathy, and cryoglobulinemic glomerulopathy were ruled out in the cases. CONCLUSION: The hydralazine-induced autoimmune phenomenon can be seen in IgM-dominant ICMGN, which should be classified as a subtype of membranoproliferative glomerulonephritis.

Crystalline silica-induced pulmonary inflammation and autoimmunity in mature adult NZBW/f1 mice: age-related sensitivity and impact of omega-3 fatty acid intervention.

OBJECTIVE: Occupational exposure to respirable crystalline silica (cSiO2) has been linked to lupus development. Previous studies in young lupus-prone mice revealed that intranasal cSiO2 exposure triggered autoimmunity, preventable with docosahexaenoic acid (DHA). This study explores cSiO2 and DHA effects in mature lupus-prone adult mice, more representative of cSiO2-exposed worker age. METHODS: Female NZBWF1 mice (14-week old) were fed control (CON) or DHA-supplemented diets. After two weeks, mice were intranasally instilled saline (VEH) or 1 mg cSiO2 weekly for four weeks. Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset. RESULTS: VEH/CON mice showed no pathology. cSiO2/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO2/CON lungs exhibited elevated cellularity, chemokines, CD3+ T-cells, CD45R + B-cells, IgG + plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. DHA supplementation mitigated all these effects. DISCUSSION: The mature adult NZBWF1 mouse used here represents a life-stage coincident with immunological tolerance breach and one that more appropriately represents the age (20-30 yr) of cSiO2-exposed workers. cSiO2-induced robust pulmonary inflammation, autoantibody responses, and glomerulonephritis in mature adult mice, surpassing effects observed previously in young adults. DHA at a human-equivalent dosage effectively countered cSiO2-induced inflammation/autoimmunity in mature mice, mirroring protective effects in young mice. CONCLUSION: These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses.

Pharmacological investigation of indole alkaloids from Alstonia scholaris against chronic glomerulonephritis.

BACKGROUND: As one of the most commonly used folk medicines in "Dai" ethno-medicine system, Alstonia scholaris (l.) R. Br. has also been used for treat "water related diseases", such as chronic kidney disease. However, few study was reported for it on the intervention of chronic glomerulonephritis (CGN). PURPOSE: To investigate the effect and potential mechanism of indole alkaloids from A. scholaris leaves in ICR mice with adriamycin nephropathy, as well as providing experimental evidence for the further application. METHODS: ICR Mice were selected for injections of adriamycin (ADR) to induce the CGN model and administered total alkaloids (TA) and four main alkaloids continuously for 42 and 28 days, respectively. The pharmacological effects were indicated by serum, urine, and renal pathological observations. The targets and pathways of indole alkaloids on CGN intervention were predicted using the network pharmacology approach, and the immortalized mice glomerular podocyte (MPC5) cells model stimulated by ADR was subsequently selected to further verify this by western blotting and RT-qPCR methods. RESULTS: TA and four major compounds dramatically reduced the levels of urinary protein, serum urea nitrogen (BUN), and creatinine (CRE) in ADR - induced CGN mice, while increasing serum albumin (ALB) and total protein (TP) levels as well as ameliorating kidney damage. Moreover, four alkaloids effected on 33 major target proteins and 153 pathways in the CGN, among which, PI3K-Akt as the main pathway, an important pathway for kidney protection by network pharmacology prediction, and then the four target proteins - HRAS, CDK2, HSP90AA1, and KDR were screened. As a result, Val-and Epi can exert a protective effect on ADR-stimulated MPC5 cells injury at a concentration of 50 µM. Furthermore, the proteins and RNA expression of HRAS, HSP90AA1, and KDR were down-regulated, and CDK2 was up-regulated after the intervention of Val-and Epi, which were supported by Western blotting and RT-qPCR. Additionally, Val-and Epi inhibited ROS production in the MPC5 cells model. CONCLUSION: This study is the first to confirm the potential therapeutic effect of alkaloids from A. scholaris on CGN. TA with major bioactive components (vallesamine and 19­epi-scholaricine) could exert protective effects against the ADR-induced CGN by regulating four key proteins: HRAS, CDK2, HSP90AA1, and KDR of the PI3K-Akt pathway.

Diagnostic dilemma: drug-induced vasculitis versus systemic vasculitis.

Drug-induced vasculitis can rarely cause inflammation and necrosis of blood vessel walls of both kidney and lung tissue. Diagnosis is challenging because of the lack of difference between systemic and drug-induced vasculitis in clinical presentation, immunological workup and pathological findings. Tissue biopsy guides diagnosis and treatment. Pathological findings must be correlated with clinical information to arrive at a presumed diagnosis of drug-induced vasculitis. We present a patient with hydralazine-induced antineutrophil cytoplasmic antibodies-positive vasculitis with a pulmonary-renal syndrome manifesting as pauci-immune glomerulonephritis and alveolar haemorrhage.

Pembrolizumab induced-C3 glomerulonephritis and RBC cast nephropathy: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly being used in the treatment of several cancers. Pembrolizumab is an anti-programmed cell death-1 (anti-PD-1) monoclonal antibody that is approved for the treatment of metastatic non-small cell lung cancer (NSCLC). Pembrolizumab-associated renal toxicity is relatively rare, even in pembrolizumab-associated glomerulonephritis. In this study, we report a rare case of pembrolizumab-induced C3 glomerulonephritis (C3GN) and RBC cast nephropathy. CASE PRESENTATION: A 68-year-old man with NSCLC was receiving treatment with pembrolizumab. After 19 cycles of pembrolizumab therapy, he presented with gross hematuria, severe lower-limb edema and oliguria. Laboratory tests revealed hypoalbuminemia, increased serum creatinine and low serum C3 level. Renal biopsy revealed a typical membranoproliferative glomerulonephritis accompanied by remarkable RBC casts in tubular cavities and tubulointerstitial infiltration of CD8-positive lymphocytes. Based on C3-only immunofluorescence deposit on glomeruli, a diagnosis of C3GN was made. Pembrolizumab was considered the cause of C3GN. Pembrolizumab was discontinued immediately, and 60 mg/day of prednisone was initiated. One dose of cyclophosphamide (400 mg, IV) was also administered. Upon treatment, his symptoms improved rapidly and serum creatinine decreased a lot. However, the patient became dialysis dependent eventually. CONCLUSION: This is the first case of C3GN with RBC cast nephropathy caused by ICIs. This rare case caused by the prolonged use of pembrolizumab further strengthens the relationship between ICIs and C3GN. Thus, periodic evaluation of urine and renal function is recommended in patients receiving pembrolizumab and other ICIs.

Tocilizumab Attenuates Anti-neutrophil Cytoplasmic Antibody-associated Nephritis Occurring during Abatacept and Adalimumab Therapy for Rheumatoid Arthritis.

We encountered an 86-year-old Japanese woman who presented with proteinuria (0.4 g/day) and hematuria (red blood cell sediment >100/high-power field), a decreased renal function (serum creatinine, 1.51 mg/dL), and elevated myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) levels (231 IU/mL) during treatment of rheumatoid arthritis with abatacept (a cytotoxic T-lymphocyte-associated antigen 4 agent) and adalimumab (a tumor necrosis factor-α agent). A kidney biopsy showed pauci-immune necrotizing glomerulonephritis, and ANCA-associated vasculitis was diagnosed. Treatment with tocilizumab (an interleukin 6 receptor antibody) monotherapy resulted in the improvement of renal findings and normalization of rheumatoid arthritis disease activity and serum ANCA levels. Tocilizumab can also suppress ANCA-associated vasculitis.

Overlap of Thrombotic Microangiopathy and Mesangial Proliferative Glomerulonephritis Caused by Combination Therapy with Atezolizumab and Bevacizumab.

Vascular endothelial growth factor inhibitors and checkpoint inhibitors are effective treatments for solid tumors. These new classes of anti-cancer agents frequently cause kidney-related side effects. Although their anti-cancer effects may be enhanced when used in combination, the severity of their kidney-related side effects is unknown. We herein report the first case of thrombotic microangiopathy and mesangial proliferative glomerulonephritis caused by combined treatment with atezolizumab and bevacizumab in a 74-year-old man with hepatocellular carcinoma. The combination therapy was discontinued and replaced with intravenous methylprednisolone followed by oral prednisolone. Subsequently, the urinary protein excretion levels declined.

High-throughput data on circular RNA reveal novel insights into chronic glomerulonephritis.

BACKGROUND: Circular RNAs (circRNAs), a unique novel type of RNA, have been widely reported to be involved in physiologic and pathologic processes in humans. However, the exact molecular pathogenesis of circRNAs in chronic glomerulonephritis (CGN) is far from clear. OBJECTIVE: This paper aims to evaluate the specific expression profile of circRNAs in renal cortex tissues from Adriamycin-induced CGN rats. METHODS: CircRNAs were screened in renal cortex tissues from 3 CGN rats and 3 control rats by using high-throughput sequencing (HTS). Then, 4 circRNAs were selected randomly for verification by quantitative real-time polymerase chain reaction (qRT-PCR). In addition, the differentially expressed (DE) circRNAs were analyzed by bioinformatics methods. RESULTS: In total, 31 significantly DE circRNAs were identified, which revealed their potential roles in CGN; in particular, we found that 4 confirmed altered circRNAs (rno-circ-RNAs 689, 3217, 1327, and 5001) might play important roles in the development of CGN. CONCLUSION: This study reveals a cluster of circRNAs that are DE in Adriamycin-induced CGN rats, which brings us closer to understanding the pathogenic mechanisms and may provide new potential targets for clinical treatment.

Glomerular diseases after immune checkpoint inhibitors use: What do We know so far?

The research and application of immune checkpoint inhibitors (ICIs) have enormously promoted the progression of tumor treatment. Gradual implementation of ICIs in clinical practice is largely limited as they exert uncontrolled collateral effects on the immune system, such as immune-related adverse events (irAEs); this includes rarely reported glomerular diseases. This study aimed to describe the clinical and pathological manifestation of ICIs-induced glomerular diseases and focused on the mechanism and therapeutic strategy for glomerular diseases associated with ICIs. The data of 53 patients with glomerular diseases related to ICIs were retrieved from the PubMed database. The most frequently reported ICIs-related glomerular diseases were pauci-immune glomerulonephritis (28.3%), podocytopathies (26.4%), and immune-complex glomerulonephritis (18.9%). Moreover, anti-PD1 antibodies were the most commonly used ICIs (71.4%). Most patients receiving ICIs discontinued the treatment (89.4%) and were initiated with steroids (87.2%). Rituximab was also useful in the treatment, especially for renal vasculitis. Rechallenging ICIs could be considered for cancer progression or as salvage therapy, where rechallenging ICI therapy with steroids may be beneficial. We believe the treatment should be personalized based on the degree of renal pathology, serum creatinine (Scr), and tumor progression to obtain a good prognosis.

Pathophysiology and system biology of rat c-BSA induced immune complex glomerulonephritis and pathway comparison with human gene sequencing data.

Immune-complex glomerulonephritis (ICGN) is a major cause of nephrotic syndrome in adults and children. Cationic BSA (c-BSA) intravenous injection could produce significant albuminuria within a short time, and is a suitable in vivo experimental animal model to investigate the pathophysiology of ICGN and for drug screening, but lack of thorough study to clarify its dynamic pathophysiological alteration so far, as well as detailed changes in mRNA and LncRNA levels. The purpose of this study is to investigate the dynamic alteration in renal function, lipid metabolism and histopathology during the progress of c-BSA induced ICGN. RNA sequencing was used to identified differentially expressed mRNA and LncRNA in kidney cortex of ICGN. Results demonstrated that c-BSA induced ICGN model could completely exhibit clinical features of immune-mediated nephrotic syndrome with gradual declining renal function, and increased albuminuria and deteriorated histopathological injuries. The correlation analysis suggested that complement activation was the most key element in mediating of ICGN. RNA sequencing using rat kidney tissues combined with Gene Expression Omnibus (GEO) data of human glomerulonephritis showed the most enriched KEGG pathways in ICGN were Toll-like receptor signaling pathway, B cell receptor and Focal adhesion. The differential lncRNAs in ICGN rats were also screened, and the lncRNA-mRNA co-expression network was constructed to clarify lncRNA role in molecular mechanism of ICGN progression. Their human homogenous lncRNAs were also identified, such as ST3GAL5-AS1 and DIO3OS, which provide the potential lncRNA targets to treat ICGN. All the differential LncRNAs in ICGN kidneys caused by MMF were also identified and provided another possible pharmacological mechanism of MMF through lncRNA regulation. In summary, the current study firstly described the dynamic physiological changes of c-BSA induced ICGN, identified most key KEGG pathways, and provided lncRNA-mRNA regulatory network in ICGN.

The efficacy and safety of tacrolimus and entecavir combination therapy in the treatment of hepatitis B virus-associated glomerulonephritis: a multi-center, placebo controlled, and single-blind randomized trial.

BACKGROUND: The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN. METHODS: Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events. RESULTS: There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29). CONCLUSIONS: In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03062813.

Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies.

Drug-induced kidney injury has historically been associated with renal tubule injury related to small molecule pharmaceuticals such as nonsteroidal anti-inflammatory drugs, antineoplastic agents, or antibiotics, but as a greater number of alternative classes of medicines such as biotherapeutics, molecular-targeted antineoplastic drugs, chimeric antigen receptor T-cell therapies, antibody-drug conjugates, oligonucleotide therapies, or other immunomodulatory drugs come to market, the presentation of drug-induced nephrotoxicity is changing. This review article describes the potential rare clinical events in drug-induced kidney injury that might be noted with these new therapies and their potential impact on patients. Potential pathogenic mechanisms related to immunogenicity, immune complex formation, and stimulation of downstream proinflammatory pathways with some of these alternative medicine classes have resulted in the potential for glomerulonephritis, acute interstitial nephritis, renal vasculitis, and other immune-mediated renal disorders in humans. This contrasts with nonclinical toxicity studies, where biologic therapies more often result in vasculitis and glomerulonephritis associated with antidrug antibodies and immunomodulatory pharmacology, and which are not always predictive of clinical effects. While nonclinical antidrug antibody-related renal disease is generally not clinically relevant, other immune-mediated nephrotoxicities associated with immunomodulatory drugs may be predictive of clinical adverse events. Fortunately, these conditions are still rare and account for a small percentage of serious adverse events in kidneys of patients.

EOS789, pan-phosphate transporter inhibitor, ameliorates the progression of kidney injury in anti-GBM-induced glomerulonephritis rats.

Hyperphosphatemia associated with chronic kidney disease (CKD) not only dysregulates mineral metabolism and bone diseases, but also strongly contributes to the progression of kidney disease itself. We have identified a novel drug for hyperphosphatemia, EOS789, that interacts with several sodium-dependent phosphate transporters (NaPi-IIb, PiT-1, and PiT-2) known to contribute to intestinal phosphate absorption. In this study, we investigated whether EOS789 could ameliorate kidney disease progression in glomerulonephritis rats. Anti-glomerular basement membrane (GBM) nephritis was induced in rats by intravenously administering two types of anti-rat GBM antibodies. We evaluated the effect of EOS789 administered in food admixture on hyperphosphatemia and kidney disease progression. In an anti-GBM nephritis rats, which exhibit a significant increase in serum phosphate and a decline in renal function, EOS789 dose-dependently improved hyperphosphatemia and EOS789 at 0.3% food admixture significantly ameliorated kidney dysfunction as shown in the decline of serum creatinine and BUN. Renal histopathology analysis showed that EOS789 significantly decreased crescent formation in glomeruli. To elucidate the mechanism underlying glomerular disease progression, human mesangial cells were used. High phosphate concentration in media significantly increased the expression of Collagen 1A1, 3A1, and αSMA mRNA in human mesangial cells and EOS789 dose-dependently suppressed these fibrotic markers. These results indicate that EOS789 prevented glomerular crescent formation caused by mesangial fibrosis by ameliorating hyperphosphatemia. In conclusion, EOS789 would not only be useful against hyperphosphatemia but may also have the potential to relieve mesangial proliferative glomerulonephritis with crescent formation.

Proximity to petrochemical industrial parks and risk of chronic glomerulonephritis.

This study determined whether individuals residing near petrochemical industrial parks (PIPs) have a higher risk of chronic glomerulonephritis (CGN). We performed population-based 1:4 case-control study by using Taiwan's National Health Insurance Research Database from 2000 to 2016. The subjects were aged 20-65 years, residing in western Taiwan, and did not have a history of any renal or urinary system disease in 2000. The case cohort included those who had at least three outpatient visits or one hospitalization between 2001 and 2016 with codes for CGN as per International Classification of Diseases (ICD)-Ninth and Tenth Revisions. Controls were randomly sampled age-, sex-, and urbanization-matched individuals without renal and urinary system diseases. Petrochemical exposure was evaluated by the distance to the nearest PIP of the residential township, and petrochemical exposure probability was examined considering the monthly prevailing wind direction. Conditional logistic regression was used to determine the association between petrochemical exposure and CGN risk. A total of 320,935 subjects were included in the final analysis (64,187 cases and 256,748 controls). After adjustment for potential confounders, living in townships within a 3-km radius of PIPs was associated with a higher risk of CGN (adjusted odds ratio [aOR] = 1.32, 95% confidence interval [CI] = 1.28-1.37). Compared with townships more than 20 km away from PIPs, those within 10 km of PIPs were associated with significantly increased risks of CGN in a dose-dependent manner. When prevailing wind was considered, townships with high exposure probability were associated with a significantly increased risk of CGN. We found that those residing near PIPs or with high petrochemical exposure probability had a higher risk of CGN. These findings highlight the need for monitoring environmental nephrotoxic substances and the renal health of residents living near PIPs.