The neurotoxicity and safety of treatment with cefepime in patients with renal failure.

BACKGROUND: Cases of cefepime neurotoxicity have been sporadically reported in patients with renal failure. The neurotoxicity of cefepime might be underestimated and the frequency of its neurotoxic effects may be insufficiently recognized. METHODS: We retrospectively reviewed the files of patients with renal failure who were treated with cefepime and who developed neurological complications. RESULTS: All 8 patients developed decreased conscience, confusion, agitation, global aphasia, myoclonus, chorea-athetosis, convulsions and coma. The latency, the period between the start of treatment and neurological deterioration, was 4,75 +/- 2,55 days (range: 1-10 days). All patients died 17 +/- 14,7 days (range: 1-42 days) after becoming symptomatic. Three of them died shortly after neurological deterioration. Five patients developed a neurological "tableau" with global aphasia. Three patients showed clinical improvement after the discontinuation of cefepime. Electroencephalography revealed diffuse slow-wave activity (delta) and triphasic sharp wave activity. These findings confirm the possible neurotoxicity of treatment with cefepime in patients with renal failure. In none of the deceased patients have we been able to directly demonstrate a causal relationship between neurotoxicity and mortality. However, when a patient treated with cefepime develops neurological deterioration or aphasia, one must be aware of cefepime's potential neurotoxicity and treatment should be stopped. CONCLUSION: We recommend that, in view of the high and unexplained mortality, the use of cefepime in patients with kidney failure should be carefully considered.

Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation.

Aristolochic acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with aristolochic acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity.

Methotrexate should not be used for patients with end-stage kidney disease.

Methotrexate is a widely used disease-modifying anti-rheumatic drug. Its effectiveness has been proven in placebo-controlled trials and in comparison with other disease-modifying anti-rheumatic drugs. The pharmacokinetics of methotrexate are highly variable and unpredictable. In patients with normal renal function, the recommended dose in rheumatoid arthritis ranges between 7.5 and 15 mg/week, but in recent years, even dosages up to 25 mg weekly are used. Toxicity includes myelosuppression, gastrointestinal adverse effects, hepatotoxicity and pneumonitis. Renal impairment and age are considered major risk factors for developing methotrexate toxicity, but studies show conflicting results. Whether methotrexate can be administered to patients with end-stage kidney disease has not been formally tested. The present case illustrates the severe side effects of low-dose methotrexate treatment in a patient with end-stage kidney disease. Seven other cases have reported similar and even more severe and irreversible consequences after low-dose regimen. In view of these side effects we strongly recommend to monitor toxicity rigorously in patients with stage 3 or stage 4 kidney disease and not to use methotrexate in patients with stage 5 kidney disease.

Quantification of renal perfusion and function on a voxel-by-voxel basis: a feasibility study.

The feasibility of a voxel-by-voxel deconvolution analysis of T(1)-weighted DCE data in the human kidney and its potential for obtaining quantification of perfusion and filtration was investigated. Measurements were performed on 14 normal humans and 1 transplant at 1.5 T using a Turboflash sequence. Signal time-courses were converted to tracer concentrations and deconvolved with an aorta AIF. Parametric maps of relative renal blood flow (rRBF), relative renal volume of distribution (rRVD), relative mean transit time (rMTT), and whole cortex extraction fraction (E) were obtained from the impulse response functions. For the normals average cortical rRBF, rRVD, rMTT, and E were 1.6 mL/min/mL (SD 0.8), 0.4 mL/mL (SD 0.1), 17s (SD 7), and 22.6% (SD 6.1), respectively. A gradual voxelwise rRBF increase is found from the center of two infarction zones toward the edges. Voxel IRFs showed more detail on the nefron substructure than ROI IRFs. In conclusion, quantitative voxelwise perfusion mapping based on deconvolved T(1)-DCE renal data is feasible, but absolute quantification requires inflow correction. rRBF maps and quantitative values are sufficiently sensitive to detect perfusion abnormality in pathologic areas, but further research is necessary to separate perfusion from extraction and to characterize the different compartments of the nephron on the (sub)voxel level.

Diabetes delaying the diagnosis of RPGN.

The present case describes the unusual association of a crescentic glomerulonephritis (GN), diabetes mellitus and a monoclonal gammopathy. After an unexplained deterioration of renal function, a kidney biopsy was performed. The finding of crescentic glomerulonephritis was unexpected. This case illustrates the usefulness of kidney biopsy in diabetes to exclude concomittant disease.

Contribution of anaemia to progression of renal disease: a debate.

It is hypothesized that anaemia contributes to the progression of renal disease via hypoxia and oxidative stress. These effects may stimulate the production of extracellular matrix by fibroblasts, increasing interstitial fibrosis and leading to tubular destruction. Recombinant human erythropoietin (r-HuEPO, epoetin) has antioxidative and anti-apoptotic properties, though these effects have yet to be demonstrated in renal cells. In theory, epoetin treatment might slow the progression of renal failure, not only by correcting anaemia but also via direct effects on tubular and vascular cell survival. Alternative hypotheses suggest, however, that epoetin could have negative effects on the kidney because of its vasoconstrictive action, which is independent of haemoglobin levels. Retrospective and prospective clinical studies clearly show that epoetin does not accelerate progression of renal disease, provided that blood pressure is well controlled. Some studies suggest that epoetin slows the progression of renal failure, although this remains a controversial issue, as all these studies have methodological limitations. Larger randomized controlled trials and meta-analysis of the existing trials are required to establish whether treatment of anaemia with epoetin can indeed slow the progression of renal disease.

Relapsing ascites and uremia due to urinary bladder leakage.

A 62-year-old female was admitted for a new episode of ascites, complicated by uremia. She had been treated 6 years earlier for bladder cancer with partial cystectomy and postoperative radiotherapy. At the work-up for both previous episodes of ascites, 6 and 24 months earlier, no definite diagnosis was made, and each time the ascites disappeared spontaneously. Also, at the third episode, the uremia resolved. Finally, explorative laparoscopy demonstrated urinary leakage from the superior portion of the bladder. This feature of vanishing and relapsing ascites is explained by intermittent covering by overlying abdominal structures and subsequent spontaneous healing. The pseudo-renal failure is caused by reabsorption of urine through the peritoneum. Only nine cases of recurring ascites and eight cases of bladder perforation after radiotherapy have been described in the literature.

Altered antioxidant defence in a mouse adriamycin model of glomerulosclerosis.

BACKGROUND: Antioxidant enzyme status changes in experimental models of chronic renal disease with glomerulosclerosis. Most of the studies are performed in rats. We now investigate whether a mouse model with more rapid development of glomerulosclerosis is suitable for the study of radical-associated renal disease. METHODS: Female BALB/c mice are injected intravenously with a single dose of adriamycin (10 mg/kg). The development of glomerular and interstitial injury is evaluated by means of renal function parameters and histology. Renal cortex activities of catalase, Cu/Zn and Mn superoxide dismutase and glutathione peroxidase are measured by enzymatic techniques, and their mRNA levels by Northern blot analysis. RESULTS: The mice develop proteinuria and hypercholesterolaemia; glomerulosclerosis is present 20 days after adriamycin injection. Involvement of reactive oxygen intermediates in the disease process is supported by an increased cortex level of glutathione (1.77+/-0.13 vs 1.31+/-0.12 micromol/g kidney; P = 0.021) and ferric iron deposition in the tubulointerstitial compartment. Glomerulosclerosis and tubulointerstitial lesions are accompanied by decreased cortex activities of catalase (0.19+/-0.01 vs 0.23+/-0.01 U/mg protein; P = 0.024), glutathione peroxidase (0.28+/-0.01 vs 0.32+/-0.01 U/mg protein; P = 0.049) and Mn superoxide dismutase (6.61+/-0.91 vs 9.25+/-0.99 U/mg protein, P = 0.020). We find decreased cortex mRNA levels only for glutathione peroxidase. CONCLUSION: The fast development of glomerulosclerosis combined with an altered antioxidant status makes this mouse adriamycin model a suitable alternative for the slower rat models.

Angiotensin II administration causes enhanced expression of glomerulosclerosis-related markers and decreased renal antioxidant enzyme activities in rats.

Angiotensin II administration to rats during 6 weeks causes decreased activity of catalase and glutathione peroxidase in renal cortex. Rats show mild hypertension, subclinical signs of renal injury, increased glomerular expression of desmin, glomerular and interstitial expression of alpha-smooth muscle actin and an increased number of ED-1-positive cells in glomeruli. An inverse correlation exists between catalase activity and glomerular alpha-smooth muscle actin expression and between glutathione peroxidase activity and glomerular desmin expression. The decrease of antioxidant enzyme activity, early after angiotensin II administration, might be an important initiating factor in the complex process leading eventually to renal sclerosis by reduction of reactive oxygen intermediate breakdown. The significant relationship between markers of sclerosis and some antioxidant enzyme activities suggests either a causative link or a common triggering factor.

Renal antioxidant enzymes and fibrosis-related markers in the rat adriamycin model.

Excessive generation of reactive oxygen intermediates can induce changes in the cellular antioxidant defence system. In this study we examine the antioxidant enzyme status and the expression of fibrosis-related marker proteins in the Adriamycin model of chronic renal failure in the rat. Twenty weeks after Adriamycin treatment, rats have overt nephrotic syndrome and renal failure with development of tubulo-interstitial fibrosis and glomerulosclerosis. Lipids accumulate in blood and in both glomeruli and tubulo-interstitial tissue. Desmin and alpha-smooth muscle actin expression increases in glomeruli and in the tubulo-interstitial area. Renal cortex antioxidant enzyme activities are decreased 20 weeks after Adriamycin injection (to 41% for catalase, to 56% for total superoxide dismutase and to 69% for glutathione peroxidase). The mRNA levels of catalase, Cu/Zn-superoxide dismutase and glutathione peroxidase-1 evaluated by Northern blot are decreased by more than 50% for catalase, Cu/Zn-superoxide dismutase and glutathione peroxidase-1. We conclude that in the rat Adriamycin-induced model of chronic renal failure with fibrosis, the combination of decreased antioxidant enzyme status in renal cortex with high concentrations of lipids in blood and renal tissue facilitates oxidative damage. Development of fibrosis is paralleled by increased expression of desmin and alpha-smooth muscle actin.

Antioxidant enzyme gene expression in rats with remnant kidney induced chronic renal failure.

Reactive oxygen intermediates play a role in chronic renal injury and glomerulosclerosis. We investigate changes in renal cortex antioxidant enzyme gene expression in the rat remnant-kidney model of chronic renal failure and compare the new data to enzyme activities published earlier. Antioxidant enzyme gene expression is evaluated by Northern blot analysis of cortex mRNA, using cDNA probes for catalase, copper/zinc-containing superoxide dismutase, and glutathione peroxidase. Catalase gene expression decreases during development of renal failure; this decrease is accompanied by decreased catalase activity during the glomerulosclerosis phase of the remnant-kidney model. Copper/zinc superoxide dismutase and glutathione peroxidase gene expression remain at a normal level during progression of the model, whereas their activities show a temporary decrease in the early remnant kidney. In the remnant-kidney model, catalase seems to be more vulnerable to reactive oxygen intermediates than superoxide dismutase and glutathione peroxidase. Our results show that antioxidant enzyme activity and gene expression do not change in the same direction at all times during disease development and that all antioxidant enzymes do not respond in the same way.

The predictive value of cardiac troponin T measurements in subjects on regular haemodialysis.

BACKGROUND: Cardiac troponin T (cTnT) is a subunit of the cardiac actin-myosin complex, which leaks into the circulation when myocardial necrosis is present. Detection of cTnT is associated with a poor outcome in patients with unstable angina, and is a useful tool for risk stratification. The value of cTnT determination in patients with renal failure has been questioned, and the specificity of cTnT in this particular group has not been established. METHODS: In the present study, 94 patients at a single centre were followed prospectively after three determinations of cTNT, at 1-month intervals. The outcome after 12 months was chosen as the end-point. cTnT was measured using both a quantitative chemiluminiscence immunoassay and a qualitative rapid bedside immunoassay on a test strip. The maximum of three measurements was used and was correlated with different parameters and outcome. The following statistical tests were performed: Kaplan-Meier analysis, Cox's proportional regression analysis for measuring survival and logistic regression for analysing factors influencing cTnT. RESULTS: Forty seven of the 94 patients had a positive cTnT by test strip defined as >0.10 ng/ml. Twenty four patients died in the follow-up period (14 from cardiovascular causes). Twenty of the 24 non-survivors had an increased cTnT by test strip and 23 had increased cTnT by laboratory immunoassay. The outcome analysed by a Cox's proportional regression analysis showed that the factors which influenced survival significantly were cTnT, the presence of ischaemic heart disease, C-reactive protein (CRP) and prealbumin. A logistic multivariate analysis revealed that age and CRP significantly influenced cTnT. A good correlation was found between cTnT determined by test strip and in the laboratory. CONCLUSION: cTnT is elevated in a large number of patients on regular haemodialysis and is a significant independent predictor of outcome. Increased cTnT is significantly predicted by age and CRP.

Recurrent gastrointestinal blood loss of obscure origin: report of an exceptional case.

A 66-year old tailor was admitted because of venous insufficiency of the left lower leg. During the hospital course, recurrent severe gastrointestinal blood loss developed. A classical approach was extended by enteroscopy and radionuclide scanning, followed by exploratory laparatomy with removal of two intra-abdominal sewing needles and a jejunal leiomyoma. After surgery, bleeding did not recur. This case illustrates the difficult diagnostic work-up of obscure gastrointestinal bleeding. It also shows that intra-abdominal sewing needles may migrate in the intestinal tract and remain silent during many years, eventually causing gastrointestinal bleeding.

Enalapril increases antioxidant enzyme activity in renal cortical tissue of five-sixths-nephrectomized rats.

In rats with five-sixths nephrectomy (remnant kidney), blood pressure, glomerulosclerosis, and proteinuria are significantly reduced by administration of the angiotensin-converting enzyme inhibitor enalapril, during 16 weeks after reduction of the nephron number. The activity of catalase in remnant-kidney cortex homogenate is not influenced by enalapril treatment; the activities of superoxide dismutase and glutathione peroxidase are significantly increased. Elevated lipid peroxidation in cortex homogenates, evaluated by malondialdehyde and 4-hydroxynonenal concentrations, is not changed by treatment. Supplementation of dietary vitamin E to enalapril treatment does not alter antioxidant enzyme activities when compared to enalapril monotherapy. These results show that enalapril improves the balance between reactive oxygen intermediates and antioxidant enzymes in the remnant-kidney cortex of the rat. This finding may in part explain the protective effect of angiotensin-converting enzyme inhibitors on the progression of glomerulosclerosis.

Odour perception in chronic renal disease.

BACKGROUND: The sense of smell plays an important role in the quality of life. Many studies have shown a declining odour perception in the elderly, as well as in subjects in poor health or nutritional state. Considering the high prevalence of poor nutritional state in renal disease and the importance of odour perception in nutrition and health, the relationship between renal function, nutritional state, and odour perception is explored in this study. METHODS: A total of 101 patients with chronic renal failure participated in the study. Thirty-eight haemodialysis patients (mean age = 64.3 years) were evaluated both before and after dialysis. Sixteen patients on peritoneal dialysis treatment (mean age = 64.0 years), 28 transplanted patients (mean age = 53.5 years, mean creatinine clearance = 64.0 ml/min) and 19 patients with varying degrees of renal insufficiency were also included (mean age = 63.7 years, mean creatinine clearance = 29.5 ml/min). Patients with cognitive deficits or upper respiratory airway diseases were excluded. A validated objective procedure was used to measure odour perception, by determining the detection threshold for isoamyl acetate (banana odour) as the lowest detectable odour concentration. RESULTS: Healthy control persons had significantly lower odour thresholds compared to patients on peritoneal (P = 0.001) and haemodialysis (P = 0.002). No significant difference was observed in odour perception between patients on peritoneal and haemodialysis (P = 0.779) and for patients on haemodialysis before and after a dialysis session. Transplanted patients had significantly better odour perception compared to matched patients on dialysis (P < 0.001). Odour perception of transplanted patients and matched healthy control persons was similar (P = 0.81). In patients with varying degrees of renal insufficiency, including healthy controls and transplanted patients, a significant positive correlation was found between odour perception and creatinine clearance (P = 0.02). A significant negative correlation was found between odour perception and serum concentration of urea (P < 0.001), serum phosphorus (P = 0.022) and protein catabolic rate (P < 0.05). Other parameters measuring nutritional status (albumin, BMI) were not correlated with odour perception. CONCLUSION: Our results show that the ability to smell is severely impaired in patients with chronic renal failure and is related to the degree of renal impairment and the degree of accumulation of uraemic toxins. After renal transplantation, patients have a normal odour perception, indicating the capacity of the olfactory system to recover once the concentration of uraemic toxins remains below a critical threshold. Acute removal of uraemic toxins by dialysis does not correct olfactory disturbances, suggesting a long lasting effect of uraemia on olfactory function.

Morphometric characteristics of peroxisomes in rats with chronic renal failure induced by five-sixth nephrectomy.

An increased H2O2 production and a decreased activity of several peroxisomal oxidases have previously been reported in kidneys of rats with five-sixth nephrectomy, a model for chronic renal failure. We investigated the morphological and morphometric characteristics of peroxisomes, the organelles in which an important part of cellular H2O2 metabolism is localized, in remnant kidneys 16 weeks after operation. The vast majority of renal peroxisomes were found in the epithelial cells of proximal tubules. The organelles were distributed throughout the cells. We observed a significant increase in size, perimeter and volume density of the peroxisomes as compared to normal kidneys. Elongated peroxisomes were less frequent. An inverse linear correlation between mean size and number of peroxisomes was found. In cortex homogenates, the activity of catalase the peroxisomal H2O2-scavenging enzyme, was significantly decreased and was inversely proportional to the mean peroxisomal diameter. The observed morphological adaptations are believed to create an unfavorable situation for the enzymatic activities in remnant kidney peroxisomes.