Renal Injury during Long-Term Crizotinib Therapy.
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ABSTRACT:
SUBMITTER: Yasuma T
PROVIDER: S-EPMC6213486 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
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Project description:Signals that drive interstitial fibrogenesis after renal ischemia reperfusion injury remain undefined. Sympathetic activation manifests even in the early clinical stages of chronic kidney disease and is directly related to disease severity. A role for renal nerves in renal interstitial fibrogenesis in the setting of ischemia reperfusion injury has not been studied. In male 129S1/SvImJ mice, ischemia reperfusion injury induced tubulointerstitial fibrosis as indicated by collagen deposition and profibrotic protein expression 4 to 16 days after the injury. Leukocyte influx, proinflammatory protein expression, oxidative stress, apoptosis, and cell cycle arrest at G2/M phase were enhanced after ischemia reperfusion injury. Renal denervation at the time of injury or up to 1 day post injury improved histology, decreased proinflammatory/profibrotic responses and apoptosis, and prevented G2/M cell cycle arrest in the kidney. Treatment with afferent nerve-derived calcitonin gene-related peptide (CGRP) or efferent nerve-derived norepinephrine in denervated and ischemia reperfusion injury-induced kidneys mimicked innervation, restored inflammation and fibrosis, induced G2/M arrest, and enhanced TGF-?1 activation. Blocking norepinephrine or CGRP function using respective receptor blockers prevented these effects. Consistent with the in vivo study, treatment with either norepinephrine or CGRP induced G2/M cell cycle arrest in HK-2 proximal tubule cells, whereas antagonists against their respective receptors prevented G2/M arrest. Thus, renal nerve stimulation is a primary mechanism and renal nerve-derived factors drive epithelial cell cycle arrest and the inflammatory cascade causing interstitial fibrogenesis after ischemia reperfusion injury.
| S-EPMC4312521 | biostudies-literature
Project description:BackgroundAdefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD).AimTo assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B.MethodsA total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria.ResultsAmong 51 patients treated for 1-10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10-year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0-3.0 mg/dL), creatinine (1.6-1.1 mg/dL), uric acid (2.7-3.8 mg/dL) and proteinuria.ConclusionsRenal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2-9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy.
| S-EPMC3443969 | biostudies-literature
Project description:The aim of this study was to evaluate serum kidney injury molecule-1 (KIM-1) as a new diagnostic marker of renal dysfunction in chronic hepatitis B (CHB) patients receiving long-term adefovir dipivoxil (ADV) treatment.We retrospectively enrolled 85 patients treated with ADV and 85 patients treated with entecavir (ETV) monotherapy, for at least 6 months. The 2 groups were matched for baseline age (± 5 years), sex, and estimated glomerular filtration rate (eGFR). Serum creatinine, cystatin C, and KIM-1 concentrations were measured, and eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-cystatin C equation, at baseline and last follow-up.eGFR decreased by 10-20% from baseline in 11/85 (14.1%) patients, 20-30% in 5/85 (5.9%), and ? 30% in 2/85 (2.4%) patients treated with ADV. Serum KIM-1 was more significantly increased after ADV treatment 86.53 (10.20-355.40) pg/mL than ETV treatment 61.54 (10.53-200.56) pg/mL (P?<?0.01). Furthermore, serum KIM-1 was positively correlated with serum cystatin C (r?=?0.47; P?<?0.001) and negatively correlated with eGFR (r?=?-0.46; P?<?0.001). The area under the receiver operating characteristic curve (AUC-ROC) of serum KIM-1 for identifying renal dysfunction in all enrolled patients was 0.94 (95% confidence interval [95% CI], 0.87 to 1.02; P?<?0.001), while the AUC-ROC of serum creatinine was only 0.82 (95% CI, 0.60 to 1.03; P?<?0.01).Serum KIM-1 is a promising new diagnostic biomarker of renal dysfunction during long-term ADV therapy for CHB patients.
| S-EPMC5591140 | biostudies-literature
Project description:The world's population is aging faster and the incidence of acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT) is increasing in elderly population. The outcome of AKI needing CRRT in elderly patients is known to be poor. However, the definitions of elderly used in the previous literatures were diverse and, there were few data that compared the long-term mortality rates of these patients with middle aged patients. This study was aimed to evaluate this issue.This study was a single-center, retrospective cohort study of patients who underwent CRRT from January 2013 to December 2015. The patients were divided into the following four age cohorts: middle-aged (55-64), young-old (65-74), middle-old (75-84), and old-old (?85). The short- and long-term mortality rates for each age cohort were compared.A total of 562 patients met the inclusion criteria. The short-term mortality rate was 57.3% in the entire cohort. Compared with the middle-aged cohort, the middle-old cohort (HR 1.48 (1.09-2.02), p = 0.012) and the old-old cohort (HR 2.33 (1.30-4.19), p = 0.005) showed an increased short-term mortality rate along with an increased SOFA score, acidemia and a prolonged prothrombin time. When we analyzed the long-term mortality rate of the 238 survived patients, the middle-old cohort (HR 3.76 (1.84-7.68), p<0.001), the old-old cohort (HR 4.40(1.20-16.10), p = 0.025), a lower BMI, the presence of liver cirrhosis, the presence of congestive heart failure and a history of sepsis were independent risk factors for the prediction of long-term mortality.Compared with the middle-aged cohort, the middle-old and the old-old cohort showed an increased short-term and long-term mortality rate. However, in the young-old cohort, neither the short-term nor the long-term mortality rate was increased.
| S-EPMC5119822 | biostudies-literature
Project description:Acute kidney injury (AKI) is a frequent complication of traumatic injury; however, long-term outcomes such as mortality and end-stage kidney disease (ESKD) have been rarely reported in this important patient population. We compared the long-term outcome of vehicle-traumatic and non-traumatic AKI requiring renal replacement therapy (AKI-RRT). This nationwide cohort study used data from the Taiwan National Health Insurance Research Database. Vehicle-trauma patients who were suffered from vehicle accidents developing AKI-RRT during hospitalization were identified, and matching non-traumatic AKI-RRT patients were identified between 2000 and 2010. The incidences of ESKD, 30-day, and long-term mortality were evaluated, and clinical and demographic associations with these outcomes were identified using Cox proportional hazards regression models. 546 vehicle-traumatic AKI-RRT patients, median age 47.6 years (interquartile range: 29.0-64.3) and 76.4% male, were identified. Compared to non-traumatic AKI-RRT, vehicle-traumatic AKI-RRT patients had longer length of stay in hospital [median (IQR):15 (5-34) days vs. 6 (3-11) days; p?<?0.001). After propensity matching with non-traumatic AKI-RRT cases with similar demographic and clinical characteristics. Vehicle-traumatic AKI-RRT patients had lower rates of long-term mortality (adjusted hazard ratio (HR), 0.473; 95% CI, 0.392-0.571; p?<?0.001), but similar rates of ESKD (HR, 1.166; 95% CI, 0.829-1.638; p?=?0.377) and short-term risk of death (HR, 1.134; 95% CI, 0.894-1.438; p?=?0.301) as non-traumatic AKI-RRT patients. In competing risk models that focused on ESKD, vehicle-traumatic AKI-RRT patients were associated with lower ESKD rates (HR, 0.552; 95% CI, 0.325-0.937; p?=?0.028) than non-traumatic AKI-RRT patients. Despite severe injuries, vehicle-traumatic AKI-RRT patients had better long-term survival than non-traumatic AKI-RRT patients, but a similar risk of ESKD. Our results provide a better understanding of long-term outcomes after vehicle-traumatic AKI-RRT.
| S-EPMC7689526 | biostudies-literature
Project description:Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model.We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group.After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05).Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury.
| S-EPMC4642846 | biostudies-other
Project description:BackgroundPapillary renal cell carcinoma (pRCC) is the 2nd most frequent histological type of kidney cancer and accounts for approximately 15% of all renal cell carcinoma. It has a poorer prognosis than clear cell RCC (ccRCC) with a lack of standard treatments.Case presentationWe report the case of a 51 year old man with a metastatic pRCC (hepatic dome and left colonic peritoneal carcinomatosis) progressive after sunitinib, with a MET amplification. The patient was enrolled in the UNICANCER-sponsored AcSé crizotinib trial (NCT02034981), designed to give an access to crizotinib for patients with tumors harboring a genomic alteration on one of the biological targets of the drug. With 2nd line crizotinib (250 mg twice/day), the patient had a very good tolerance, a partial response in the target lesions using RECIST 1.1, and a 19 months' clinical efficacy.ConclusionsIn metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option.
| S-EPMC6251103 | biostudies-literature
Project description:These samples comprise the full analysis of liver function during response to thermal injury. Keywords: Time Course
2006-08-30 | GSE5647 | GEO
Project description:The association between acute kidney injury (AKI) and long-term renal function after radical nephrectomy has not been evaluated fully. We reviewed 558 cases of radical nephrectomy. Postoperative AKI was defined by the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria. Values of estimated glomerular filtration rate (eGFR) were collected up to 36 months (median 35 months) after surgery. The primary outcome was new-onset chronic kidney disease (CKD) stage 3a or higher or all-cause mortality within three years after nephrectomy. The functional change ratio (FCR) of eGFR was defined as the ratio of the most recent GFR (24-36 months after surgery) to the new baseline during 3-12 months. A multivariable Cox proportional hazard regression analysis for new-onset CKD and a multivariable linear regression analysis for FCR were performed to evaluate the association between AKI and long-term renal outcomes. A correlation analysis was performed with the serum creatinine ratio and used to determine AKI and FCR. AKI occurred in 43.2% (n = 241/558) and our primary outcome developed in 40.5% (n = 226/558) of patients. The incidence of new-onset CKD was significantly higher in patients with AKI than those without at all follow-up time points after surgery. The Cox regression analysis showed a graded association between AKI and our primary outcome (AKI stage 1: Hazard ratio 1.71, 95% confidence interval 1.25-2.32; AKI stage 2 or 3: Hazard ratio 2.72, 95% confidence interval 1.78-4.10). The linear regression analysis for FCR showed that AKI was significantly associated with FCR (? = -0.168 ± 0.322, p = 0.011). There was a significant negative correlation between the serum creatinine ratio and FCR. In conclusion, our analysis demonstrated a robust and graded association between AKI after radical nephrectomy and long-term renal functional deterioration.
| S-EPMC7141119 | biostudies-literature
Project description:BackgroundThe optimal time to initiate renal replacement therapy (RRT) in intensive care unit (ICU) patients with acute kidney injury (AKI) is unclear. We examined the impact of early RRT on long-term mortality, risk of chronic kidney disease (CKD), and end-stage renal disease (ESRD).MethodsThis cohort study included all adult patients treated with continuous RRT in the ICU at Aarhus University Hospital, Skejby, Denmark (2005-2015). Data were obtained from a clinical information system and population-based registries. Early treatment was defined as RRT initiation at AKI stage 2 or below, and late treatment was defined as RRT initiation at AKI stage 3. Inverse probability of treatment (IPT) weights were computed from propensity scores. The IPT-weighted cumulative risk of CKD (estimated glomerular filtration rate < 60 ml/minute/1.73 m2), ESRD, and mortality was estimated and compared using IPT-weighted Cox regression.ResultsThe mortality, CKD, and ESRD analyses included 1213, 303, and 617 patients, respectively. The 90-day mortality in the early RRT group was 53.6% compared with 46.0% in the late RRT group (HR 1.24, 95% CI 1.03-1.48). The 90-day to 5-year mortality was 37.7% and 41.5% in the early and late RRT groups, respectively (HR 0.95, 95% CI 0.70-1.29). The 5-year risk of CKD was 35.9% in the early RRT group and 44.9% in the late RRT group (HR 0.74, 95% CI 0.46-1.18). The 5-year risk of ESRD was 13.3% in the early RRT group and 16.7% in the late RRT group (HR 0.79, 95% CI 0.47-1.32).ConclusionsEarly initiation was associated with increased 90-day mortality. In patients surviving to day 90, early initiation was not associated with a major impact on long-term mortality or risk of CKD and ESRD. Despite potential residual confounding due to the observational design, our findings do not support that early RRT initiation is superior to late initiation.
| S-EPMC5745999 | biostudies-literature