- Using chemical-induced gene expression in cultured human cells to predict chemical toxicity. [Journal Article]
- CRChem Res Toxicol 2016 Oct 21
- Chemical toxicity is conventionally evaluated in animal models. However, animal models are resource intensive; moreover, they face ethical and scientific challenges because the outcomes obtained by a...
Chemical toxicity is conventionally evaluated in animal models. However, animal models are resource intensive; moreover, they face ethical and scientific challenges because the outcomes obtained by animal testing may not correlate with human responses. To develop an alternative method for assessing chemical toxicity, we investigated the feasibility of using chemical-induced genome-wide expression changes in cultured human cells to predict the potential of a chemical to cause specific organ injuries in humans. We first created signatures of chemical-induced gene expression in a vertebral-cancer of the prostate cell line for ~15,000 chemicals tested in the U.S. National Institutes of Health Library of Integrated Network-based Cellular Signatures program. We then used the signatures to create naïve Bayesian prediction models for chemical-induced human liver cholestasis, interstitial nephritis, and long QT syndrome. Detailed cross-validation analyses indicated that the models were robust with respect to false positives and false negatives in the samples we used to train the models, and could predict the likelihood that chemicals would cause specific organ injuries. In addition, we performed a literature search for drugs and dietary supplements, not formally categorized as causing organ injuries in humans but predicted by our models to be most likely to do so. We found a high percentage of these compounds associated with case reports of relevant organ injuries, lending support to the idea that in vitro cell-based experiments can be used to predict the toxic potential of chemicals. We believe that this approach, combined with a robust technique to model human exposure to chemicals, may serve as a promising alternative to animal-based chemical toxicity assessment.
- Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis. [Journal Article]
- PlosPLoS One 2016; 11(10):e0164423
- Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longi...
Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNα-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly useful for preclinical research, robustly exhibiting many characteristics reminiscent of human disease. These include i) a stronger upregulation of the cytosolic nucleic acid sensing pathway, which is thought to be key component of the pathogenesis of the human disease, and ii) more prominent kidney interstitial inflammation and fibrosis, which have been both associated with poor prognosis in human LN. To our knowledge, this is the only accelerated model of LN that exhibits a robust tubulointerstitial inflammatory and fibrosis response. Taken together our data show that the pristane-SNF1 model is a novel accelerated model of LN with key features similar to human disease.
- Differences in pathological characteristics and laboratory indicators in adult and pediatric patients with Henoch-Schönlein purpura nephritis. [Journal Article]
- JHJ Huazhong Univ Sci Technolog Med Sci 2016; 36(5):659-666
- We aimed to investigate the differences in renal histopathological changes and laboratory parameters between adult and pediatric patients with Henoch-Schönlein purpura nephritis (HSPN), and to analyz...
We aimed to investigate the differences in renal histopathological changes and laboratory parameters between adult and pediatric patients with Henoch-Schönlein purpura nephritis (HSPN), and to analyze the correlation between laboratory parameters and renal histopathological grading. A total of 139 patients diagnosed with HSPN between September 2010 and December 2014 at the First Hospital of Jilin University, China, were retrospectively reviewed. The clinical and pathological characteristics were examined and compared between the adult and the pediatric patients. A majority of adult (75.0%) and pediatric (66.2%) patients were categorized as pathological grade III HSPN. Adults having crescent lesions, interstitial fibrosis and renal artery involvement significantly outnumbered child counterparts (all P<0.05). Pathological grading showed a positive correlation with 24-h urine protein (r=0.307, P=0.009), microalbuminuria (r=0.266, P=0.000) and serum globulin (r=0.307, P=0.014), and a negative correlation with serum albumin (r=0.249, P=0.037) in pediatric patients with HSPN. Among adult patients with HSPN, histopathological grading showed a positive correlation with 24-h urine protein (r=0.294, P=0.015), microalbuminuria (r=0.352, P=0.006), α1-microglobulin (r=0.311, P=0.019) and immunoglobulin G (r=0.301, P=0.023) in urine, and serum creatinine (r=0.292, P=0.018). Further, a negative correlation between serum albumin and pathological grading was also observed (r=0.291, P=0.018). In conclusion, the severity of renal pathological lesions in HSPN patients is well reflected by the levels of proteinuria. Adult patients have more severe renal histopathological changes than pediatric patients.
- Reverse osmosis plant maintenance and efficacy in chronic kidney disease endemic region in Sri Lanka. [Journal Article]
- EHEnviron Health Prev Med 2016 Oct 15
- CONCLUSIONS: The RO process reduces the impurities in water available to many individuals within CINAC endemic regions. However, there variation in maintenance, quality management, and day-to-day care between operators can be a cause for concern. This variability can affect the quality of water produced by RO plant, its maintenance cost and lifespan. Thus, uniform regulation and training is needed to reduce cost of maintenance and increase the efficacy of RO plants.
- Serum Cytokines Th1, Th2, and Th17 Expression Profiling in Active Lupus Nephritis-IV: From a Southern Chinese Han Population. [Journal Article]
- MIMediators Inflamm 2016; 2016:4927530
- Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant T cell immune response. Diffuse proliferative lupus nephritis (LN-IV) is the most common, severe, and acti...
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant T cell immune response. Diffuse proliferative lupus nephritis (LN-IV) is the most common, severe, and active form of lupus nephritis. In this study, we investigated the production of Th1, Th2, and Th17 cytokines in prediction of active form of LN-IV. ProcartaPlex multiplex immunoassays panels were used for detection of serum Th1, Th2, and Th17 cytokines profiling. Th1 and Th17 cytokines (IL-18, IFN-γ, IL-12p70, IL-6, and IL-17A) were considerably expressed in the serum of lupus nephritis IV patients in comparison to the healthy control. However, only IL18 and IL6 were higher in class IV versus class III lupus nephritis. Importantly, the ratios of Th1/Th2 (IL-18/IL-4) and Th17/Th2 (IL-17A/IL-4) were significantly elevated in LN-IV when compared with LN-III, LN-V, and healthy controls. Consistently, the serum cytokines IL-18, IL-17A, and IFN-γ were markedly expressed in LN-IV patient glomeruli and interstitial tissue compared to other classes of LN by IHC. ROC further suggests that IL-18 was a potential marker for LN-IV. The data from our study suggests that the early detection and quantification of these cytokines may help in prediction of active form of LN-IV.
- Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. [Journal Article]
- NDNephrol Dial Transplant 2016 Oct 13
- Increase in the prevalence of chronic kidney disease (CKD) is observed in Central America, Sri Lanka and other tropical countries. It is named chronic interstitial nephritis in agricultural communiti...
Increase in the prevalence of chronic kidney disease (CKD) is observed in Central America, Sri Lanka and other tropical countries. It is named chronic interstitial nephritis in agricultural communities (CINAC). CINAC is defined as a form of CKD that affects mainly young men, occasionally women. Its aetiology is not linked to diabetes, hypertension, glomerulopathies or other known causes. CINAC patients live and work in poor agricultural communities located in CINAC endemic areas with a hot tropical climate, and are exposed to toxic agrochemicals through work, by ingestion of contaminated food and water, or by inhalation. The disease is characterized by low or absent proteinuria, small kidneys with irregular contours in CKD stages 3-4 presenting tubulo-interstitial lesions and glomerulosclerosis at renal biopsy. Although the aetiology of CINAC is unclear, it appears to be multifactorial. Two hypotheses emphasizing different primary triggers have been proposed: one related to toxic exposures in the agricultural communities, the other related to heat stress with repeated episodes of dehydration heath stress and dehydration. Existing evidence supports occupational and environmental toxins as the primary trigger. The heat stress and dehydration hypothesis, however, cannot explain: why the incidence of CINAC went up along with increasing mechanization of paddy farming in the 1990s; the non-existence of CINAC in hotter northern Sri Lanka, Cuba and Myanmar where agrochemicals are sparsely used; the mosaic geographical pattern in CINAC endemic areas; the presence of CINAC among women, children and adolescents who are not exposed to the harsh working conditions; and the observed extra renal manifestations of CINAC. This indicates that heat stress and dehydration may be a contributory or even a necessary risk factor, but which is not able to cause CINAC by itself.
- Ertapenem-Induced Acute Interstitial Nephritis (AIN) in a Case of Protein S Deficiency and Factor V Leiden Mutation with Deep Vein Thrombosis. [Case Reports]
- JAJ Assoc Physicians India 2016; 64(3):85-86
- We present a case of 58 years old male patient, who presented with high fever for which injection Ertapenem was started empirically at Dubai hospital. Patient was a known case of Deep vein thrombosis...
We present a case of 58 years old male patient, who presented with high fever for which injection Ertapenem was started empirically at Dubai hospital. Patient was a known case of Deep vein thrombosis of left leg since 5 years on warfarin therapy. Patient came to India for high fever and further management. Patient developed proteinuria with high creatinine and urinary abnormalities. Renal biopsy revealed acute interstitial nephritis (AIN). In addition, he was diagnosed to have protein S deficiency with Factor V Leiden mutation.
- Successful management of acute interstitial nephritis in two cases of disseminated tuberculosis. [Journal Article]
- TTuberculosis (Edinb) 2016 Sep 28
- Acute interstitial nephritis (AIN) is characterized by an inflammatory infiltrate in the kidney interstitium and a decline in the creatinine clearance. Medications used for the treatment of tuberculo...
Acute interstitial nephritis (AIN) is characterized by an inflammatory infiltrate in the kidney interstitium and a decline in the creatinine clearance. Medications used for the treatment of tuberculosis have been implicated in the development of AIN, but there is limited data on how to manage AIN in this setting and which medications and dosages should be used to treat tuberculosis once AIN occurs. We describe two cases of AIN in the setting of disseminated tuberculosis in which AIN was successfully managed. It is recommended that Infectious Diseases and Nephrology be involved early in the care of these patients, preferably in an inpatient setting in order to expedite diagnosis and management.
- Clinically Relevant Reactivation of Polyomavirus BK (BKPyV) in HLA-A02-Positive Renal Transplant Recipients Is Associated with Impaired Effector-Memory Differentiation of BKPyV-Specific CD8+ T Cells. [Journal Article]
- PPPLoS Pathog 2016; 12(10):e1005903
- Polyomavirus BK (BKPyV) frequently reactivates in immunosuppressed renal transplant recipients (RTRs) and may lead to graft loss due to BKPyV-induced interstitial nephritis (BKVN). Little is known on...
Polyomavirus BK (BKPyV) frequently reactivates in immunosuppressed renal transplant recipients (RTRs) and may lead to graft loss due to BKPyV-induced interstitial nephritis (BKVN). Little is known on the differentiation of CD8+ T cells targeting BKPyV in RTRs. Here we investigated whether BKPyV-specific CD8+ T cell differentiation differs in RTRs with varying degrees of BKPyV reactivation and/or BKVN. Using combinatorial encoding with tetramers carrying BKPyV major capsid protein (VP1) and large T antigen protein (LTAG) epitopes, we investigated CD8+ T cell responses to BKPyV in longitudinally obtained PBMC samples from 46 HLA-A02-positive RTRs and 20 healthy adults. We were also able to isolate BKPyV-specific CD8+ T cells from five renal allografts, two of which were affected by BKVN. Before transplantation, BKPyV-specific CD8+ T cells targeting VP1 and LTAG epitopes appeared predominantly as central-memory and CD27+/CD28+ effector-memory (TEM), and naïve-like PD-1-expressing cells, respectively. After viral reactivation, BKPyV-specific CD8+ T cells assumed CD28- TEM and TEMRA states in patients who were able to control BKPyV, whereas differentiation lagged behind in patients with severe viral reactivation or BKVN. Furthermore, VP1-specific CD69+/CD103+ tissue-resident memory (TRM) cells accumulated in BKVN-affected allografts but lacked signs of effector differentiation. In contrast, granzyme B-expressing effector cells were detected in allografts not affected by BKVN. In conclusion, effector-memory differentiation of BKPyV-specific CD8+ T cells in patients with high viral load or BKVN is impaired. Further characterization of the specific mechanisms behind this altered cellular differentiation is necessary to develop therapies that can prevent the emergence of BKVN.
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- Significant Acute Kidney Injury Due to Non-steroidal Anti-inflammatory Drugs: Inpatient Setting. [Journal Article]
- PPharmaceuticals (Basel) 2010 Apr 26; 3(4):1279-1285
- In the United States non-steroidal anti-inflammatory drugs (NSAID) are freely available over-the-counter. Because of the adverse effects on the kidneys and the popularity of these drugs, unregulated ...
In the United States non-steroidal anti-inflammatory drugs (NSAID) are freely available over-the-counter. Because of the adverse effects on the kidneys and the popularity of these drugs, unregulated use of NSAIDs is an under recognized and potentially dangerous problem. Fifteen inpatients, mean age of 15.2 ± 2.3 years (five males, 10 females), were referred to nephrology for acute kidney injury. All patients admitted to taking ibuprofen and six also consumed naproxen. None of the patients had underlying renal diseases at the time of admission. Nine patients had proteinuria and 12 had hematuria (including one with gross hematuria). One patient had nephrotic syndrome but the condition resolved spontaneously without steroids and has remained in remission for four years. Two patients required dialysis. Only one of the dialyzed patients required steroid therapy for recovery of renal function. The mean duration of hospitalization was 7.4 ± 5.5 days. The serum creatinine peaked at 4.09 ± 4.24 (range 1.2-15.3) mg/dL. All patients recovered renal function with normalization of serum creatinine to 0.71 ± 0.15 mg/dL. The estimated GFR (glomerular filtration rate) at peak of renal failure was 38.2 ± 20.5 mL/min but did improve to a baseline of 134 ± 26.2 mL/min (range 89-177, p < 0.01). However, the duration from onset to normalization of serum creatinine was 37 ± 42 days indicating that majority of patients had abnormal renal function for a prolonged period. In conclusion, NSAIDs pose a significant risk of renal failure for significant duration and as an entity may be under recognized.