Acute cadmium chloride administration induces hepatic and renal CYP2A5 mRNA, protein and activity in the mouse: involvement of transcription factor NRF2

Modulation of the cytochrome P450 (CYP) monooxygenase system by cadmium was investigated in male, adult DBA/2J mice treated with a single dose (16 mumol/kg body weight, i.p.) of cadmium chloride (CdCl2). Total CYP content of liver and kidney microsomes decreased maximally (56% and 85%, respectively) 24 and 18 h, respectively, after CdCl2 treatment. Progressive increases of hepatic coumarin 7-hydroxylase (COH) activity; indicative of CYP2A5 activity, relative to the total CYP content were seen at 8 h (2-fold), 12 h (3-fold), 18 h (12-fold), and 24 h (15-fold). Similar changes were seen in the kidney. Liver and kidney CYP2A5 mRNA levels increased maximally 12 and 4 h after treatment and decreased to almost half 6 h later. In contrast, kidney and liver CYP2A5 protein levels increased maximally at 18 and 24 h. The CYP2A5 mRNA levels in the kidney and liver increased after Cd treatment in Nrf2 +/+ but not in Nrf2 -/- mouse. This study demonstrates that hepatic and kidney CYP2A5 is upregulated by cadmium with a somewhat faster response in the kidney than the liver. The strong upregulation of the CYP2A5 both at mRNA and enzyme activity levels, with a simultaneous decrease in the total CYP concentration suggest an unusual mode of regulation of CYP2A5 in response to cadmium exposure, amongst the CYP enzymes. The observed decrease in the mRNA but not in protein levels after maximal induction may suggest involvement of post-trancriptional mechanisms in the regulation. Upregulation of CYP2A5 by cadmium in the Nrf2 +/+ mice but not in the Nrf2 -/- mice indicates a role for this transcription factor in the regulation. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Effect of pravastatin on cardiovascular events in people with chronic kidney disease

Background - Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results - We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin ( 40 mg daily) versus placebo. Of 19 700 subjects, 4491 ( 22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m(2) body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome ( adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome ( HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function ( HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD ( adjusted HR 0.86, 95% CI 0.74 to 1.00, P = 0.045). Conclusions - Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

Acute cadmium chloride administration induces hepatic and renal cytochrome P450 2A5 in the mouse

Modulation of the cytochrome P450 (CYP) monooxygenase system by cadmium was investigated in male, adult DBA/2J mice treated with a single dose (16 Amol/kg body weight, i.p.) of cadmium chloride (CdCl2) at various time points. The total CYP content of kidney microsomes started to decrease 4 hours earlier than in the liver (P < 0.05), with maximal decreases at 24 hours of 56% and 85% in the liver and kidney, respectively. In contrast, both hepatic and renal coumarin 7-hydroxylase (COH) activity (indicative of CYP2A5 activity) relative to total CYP content started to progressively increase at 8 hours, with renal activity 61 times higher than the hepatic activity. Maximum increases were observed, 15-fold in the liver and 64-fold in the kidney after 24 hours. Liver and kidney CYP2A5 mRNA levels increased maximally 12 and 4 hours after treatment, respectively and decreased to almost half 6 hours later. In contrast, kidney and liver CYP2A5 protein levels increased maximally at 18 and 24 hours. This study demonstrates that hepatic and renal CYP2A5 is upregulated by cadmium with a faster response in the kidney than in the liver. This observation is concordant with the fact that kidney is the target organ for cadmium toxicity. The observed increase in the mRNA but not in protein levels after maximal induction suggests involvement of post-transcriptional mechanisms in the regulation of CYP2A5 expression by cadmium.

Role of oxidative stress in age-associated chronic kidney pathologies

The kidneys exhibit age-associated deterioration in function via a loss of 20% to 25% kidney mass, particularly from the renal cortex and increased fibrosis. Oxidative stress has been found to mediate age-associated renal cell injury and cell death, particularly apoptosis. Oxidative stress results from an imbalance between the levels of free radicals generated during aerobic metabolism, inflammation, and infection and the safe breakdown of these species by endogenous and exogenous scavengers. Other factors may influence these pathologies. For example, growth hormone and caloric restriction have been shown to influence life span, although neither method of prolonging life is likely to find general acceptance in humans. Some genetic knockout models offer promise; for example, knockout of the p66 isoform of the Shc gene in mice increases life span by 30%, but appetite, size, and fertility are retained. Whether the increase in life span is via increased kidney health is not yet clear, but decreasing the age-related renal pathologies will no doubt aid in increasing life span and health in general. This review looks at the role and modulation of factors that influence life span, in particular modulation of oxidative stress, with particular relevance to age-related renal pathologies. (C) 2005 by the National Kidney Foundation, Inc.

Differential expression of muscle damage in humans following acute fast and slow velocity eccentric exercise

We sought to determine if the velocity of an acute bout of eccentric contractions influenced the duration and severity of several common indirect markers of muscle damage. Subjects performed 36 maximal fast (FST, n=8: 3.14 rad center dot s(-1)) or slow (SLW, n=7: 0.52 rad center dot s(-1)) velocity isokinetic eccentric contractions with the elbow flexors of the non-dominant arm. Muscle soreness, limb girth, plasma creatine kinase (CK) activity, isometric torque and concentric and eccentric torque at 0.52 and 3.14 rad center dot s(-1) were assessed prior to and for several days following the eccentric bout. Peak plasma CK activity was similar in SLW (4030 +/- 1029 U center dot l(-1)) and FST (5864 +/- 2664 U center dot l(-1)) groups, (p > 0.05). Both groups experienced similar decrement in all strength variables during the 48 hr following the eccentric bout. However, recovery occurred more rapidly in the FST group during eccentric (0.52 and 3.14 rad center dot s(-1)) and concentric (3.14 rad center dot s(-1)) post-testing. The severity of muscle soreness was similar in both groups. However, the FST group experienced peak muscle soreness 48 hr later than the SLW group (24 hr vs. 72 hr). The SLW group experienced a greater increase in upper arm girth than the FST group 20 min, 24 hr and 96 hr following the eccentric exercise bout. The contraction velocity of an acute bout of eccentric exercise differentially influences the magnitude and time course of several indirect markers of muscle damage.

Six-month outcome for dysphagia following traumatic brain injury: Radiological assessment

The coexistence of a swallowing impairment, or dysphagia, can severely impact upon the medical condition and recovery of a child with traumatic brain injury (TBI; Logemann, Pepe, & Mackay, 1994). Despite this fact, there is limited data that provide evidence of the progression or outcome of dysphagia in the pediatric population post-TBI (Rowe, 1999). The present study aimed to (1) provide a prospective radiologically based profile of swallowing outcome and (2) determine the clinical significance of any persistent physiological swallowing deficits by investigating the presence/absence of any coexistent respiratory complications. Seven children with moderate/severe TBI were evaluated via an initial videofluoroscopic swallowing assessment (VFSS) at an average of 24.1 days postinjury, during the acute phase of management. A follow-up VFSS was conducted at an average of 7 months, 3 weeks postinjury. The physiological impairment, swallowing safety, swallowing efficiency, and functional swallowing outcomes of the acute phase post-TBI were compared with reassessment results at 6 months post-TBI. The presence/absence of lower respiratory tract infection/respiratory complications in the past 6 months postinjury were recorded.VFSS revealed a number of residual physiological oropharyngeal swallowing impairments and reduced swallowing efficiency. However, all participants presented with clinically safe and functional swallowing outcomes at 6 months post-TBI, with no recent history of respiratory complication. This study indicates good functional swallowing and respiratory outcomes for patients at 6-months post-TBI despite the presence of persistent physiological swallowing impairment.

Physical and psychological factors predict outcome following whiplash injury

Predictors of outcome following whiplash injury are limited to socio-demographic and symptomatic factors, which are not readily amenable to secondary and tertiary intervention. This prospective study investigated the predictive capacity of early measures of physical and psychological impairment on pain and disability 6 months following whiplash injury. Motor function (ROM; kinaesthetic sense; activity of the superficial neck flexors (EMG) during cranio-cervical flexion), quantitative sensory testing (pressure, thermal pain thresholds, brachial plexus provocation test), sympathetic vasoconstrictor responses and psychological distress (GHQ-28, TSK, IES) were measured in 76 acute whiplash participants. The outcome measure was Neck Disability Index scores at 6 months. Stepwise regression analysis was used to predict the final NDI score. Logistic regression analyses predicted membership to one of the three groups based on final NDI scores (< 8 recovered, 10-28 mild pain and disability, > 30 moderate/severe pain and disability). Higher initial NDI score (1.007-1.12), older age (1.03-1.23), cold hyperalgesia (1.05-1.58), and acute post-traumatic stress (1.03-1.2) predicted membership to the moderate/severe group. Additional variables associated with higher NDI scores at 6 months on stepwise regression analysis were: ROM loss and diminished sympathetic reactivity. Higher initial NDI score (1.03-1.28), greater psychological distress (GHQ-28) (1.04-1.28) and decreased ROM (1.03-1.25) predicted subjects with persistent milder symptoms from those who fully recovered. These results demonstrate that both physical and psychological factors play a role in recovery or non-recovery from whiplash injury. This may assist in the development of more relevant treatment methods for acute whiplash. (c) 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Interfaces between cardiovascular and kidney disease among Aboriginal Australians

Rates of kidney disease among several indigenous groups have been shown to be substantially higher than corresponding non-indigenous groups. This excess has been clearly shown among Aboriginal Australians with respect to both end-stage kidney disease and early kidney disease. Rates of cardiovascular disease among Aboriginal Australians are also very high, as are rates of diabetes, smoking, and possibly overweight and obesity. These factors have been traditionally linked with cardiovascular and renal disease as part of a broader metabolic syndrome. However, the links and interfaces between cardiovascular and kidney disease in this environment extend beyond these traditional factors. The factors associated with atherosclerosis have expanded in recent years to include markers of inflammation, some infection, antioxidants, and other non-traditional risk factors. Given the high rates of acute infection and poor living conditions endured by many indigenous people, one might expect these non-traditional risk factors to be highly prevalent. In this review, we explore the relationships between markers of inflammation, some serological markers of infection, and other selected markers and both cardiovascular and renal disease. In doing so, we demonstrate links between kidney and cardiovascular disease at a number of levels, beyond the traditional cardiovascular/renal risk factors. Many of these factors are beyond the control of the individual or even community; addressing these issues a broader focus and biopsychosocial model. (C) 2005 by the National Kidney Foundation, Inc.

Physical and psychological factors maintain long-term predictive capacity post-whiplash injury

Higher initial levels of pain and disability, older age, cold hyperalgesia, impaired sympathetic vasoconstriction and moderate post-traumatic stress symptoms have been shown to be associated with poor outcome 6 months following whiplash injury. This study prospectively investigated the predictive capacity of these variables at a long-term follow-up. Sixty-five of an initial cohort of 76 acutely injured whiplash participants were followed to 2-3 years post-accident. Motor function (ROM; kinaesthetic sense; activity of the superficial neck flexors (EMG) during cranio-cervical flexion), quantitative sensory testing (pressure, thermal pain thresholds and brachial plexus provocation test), sympathetic vasoconstrictor responses and psychological distress (GHQ-28, TSK and IES) were measured. The outcome measure was Neck Disability Index (NDI) scores. Participants with ongoing moderate/severe symptoms at 2-3 years continued to manifest decreased ROM, increased EMG during cranio-cervical flexion, sensory hypersensitivity and elevated levels of psychological distress when compared to recovered participants and those with milder symptoms. The latter two groups showed only persistent deficits in cervical muscle recruitment patterns. Higher initial NDI scores (OR 1.00-1.1), older age (OR 1.00-1.13), cold hyperalgesia (OR 1.1-1.13) and post-traumatic stress symptoms (OR 1.03-1.2) remained significant predictors of poor outcome at long-term follow-up (r(2) = 0.56). The robustness of these physical and psychological factors suggests that their assessment in the acute stage following whiplash injury will be important. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Baseline serum lipids and renal function in chronic kidney disease patients entering the LORD trial

Objective: Previous studies investigating associations between serum lipids and renal disease have generally not taken into account dietary intake or physical activity - both known to influence circulating lipids. Furthermore, inclusion of patients on HMG-CoA reductase inhibitors may also have influenced findings due to the pleiotropic effect of this medication. Therefore, the aim of this study is to determine the relationships between serum lipids and renal function in a group of patients not taking lipid-lowering medication and taking into account dietary intake and physical activity. Methods: Data from 100 patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial were used in this study. Patients were included with serum creatinine > 120 mu mol/l, and excluded if they were taking lipid-lowering medication. Unadjusted and adjusted relationships were determined between fasting serum lipid concentrations (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol/HDL ratio) and measures of renal function (estimated glomerular filtration rate (eGFR), creatinine clearance and serum creatinine) and urinary protein excretion. Results: Significant (p < 0.05) negative unadjusted relationships were found between lipids (total cholesterol, LDL and HDL cholesterol) and serum creatinine. In support of these findings, logarithmically-transformed lipids (total cholesterol, LDL and HDL cholesterol) were significantly associated with eGFR and creatinine clearance although the effects were of a smaller magnitude. Adjustment for dietary saturated fat intake and physical activity did not substantially change these effects. Conclusion: These data do not support the premise that lipids are associated with renal dysfunction in patients with normocholesterolemia.

Novel renoprotective actions of erythropoietin: New uses for an old hormone

Erythropoietin (EPO) has been used widely for the treatment of anaemia associated with chronic kidney disease and cancer chemotherapy for nearly 20 years. More recently, EPO has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of cytoprotective cellular responses, including mitogenesis, angiogenesis, inhibition of apoptosis and promotion of vascular repair through mobilization of endothelial progenitor cells from the bone marrow. Administration of EPO or its analogue, darbepoetin, promotes impressive renoprotection in experimental ischaemic and toxic acute renal failure, as evidenced by suppressed tubular epithelial apoptosis, enhanced tubular epithelial proliferation and hastened functional recovery. This effect is still apparent when administration is delayed up to 6 h after the onset of injury and can be dissociated from its haematological effects. Based on these highly encouraging results, at least one large randomized controlled trial of EPO therapy in ischaemic acute renal failure is currently underway. Preliminary experimental and clinical evidence also indicates that EPO may be renoprotective in chronic kidney disease. The purpose of the present article is to review the renoprotective benefits of different protocols of EPO therapy in the settings of acute and chronic kidney failure and the potential mechanisms underpinning these renoprotective actions. Gaining further insight into the pleiotropic actions of EPO will hopefully eventuate in much-needed, novel therapeutic strategies for patients with kidney disease.

Regrow or repair: Potential regenerative therapies for the kidney

Regenerative medicine is being heralded in a similar way as gene therapy was some 15 yr ago. it is an area of intense excitement and potential, as well as myth and disinformation. However, with the increasing rate of end-stage renal failure and limited alternatives for its treatment, we must begin to investigate seriously potential regenerative approaches for the kidney. This review defines which regenerative options there might be for renal disease, summarizes the progress that has been made to date, and investigates some of the unique obstacles to such treatments that the kidney presents. The options discussed include in situ organ repair via bone marrow recruitment or dedifferentiation; ex vivo stem cell therapies, including both autologous and nonautologous options; and bioengineering approaches for the creation of a replacement organ.