Serum tobramycin levels following delivery of tobramycin (Tobi) via eFlow advanced nebuliser in children with cystic fibrosis.

BACKGROUND: Safety and toxicity data for nebulised tobramycin are mainly derived from use of the Pari LC Plus nebuliser, yet many centres are now using advanced nebulisers, such as the eFlow. METHODS: Ten children (ages 2-16years) receiving 300mg TOBI via eFlow for clinical reasons participated. Serum tobramycin levels were obtained 1h post nebulisation. Nine provided samples for urinary NAG, and 10 underwent audiology. RESULTS: Tobramycin levels were >1mg/L in 3 children (maximum 3.8, 2 children aged 2years). Urine NAG/creatinine levels were raised (>0.94micromol/min/mmol) in 5 children, 1 of these had a tobramycin level of >1mg/L. One patient had high frequency hearing loss. CONCLUSION: Serum tobramycin levels over 1mg/L can occur 1h post 300mg TOBI delivered by eFlow. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.

Randomized clinical trial of the effects of methylprednisolone on renal function after major vascular surgery.

BACKGROUND: Perioperative renal dysfunction following abdominal aortic aneurysm (AAA) repair is multifactorial and may involve hypotension, hypoxia and ischaemia-reperfusion injury. Studies of cardiac and hepatic transplant surgery have demonstrated beneficial effects on renal function of high-dose methylprednisolone administered before surgery. METHODS: Twenty patients undergoing elective open AAA repair were randomized to receive either methylprednisolone 10 mg/kg or dextrose (control) before induction of anaesthesia. Blood was analysed for a panel of cytokines representative of T helper cell type 1 and 2 subsets. Urine was analysed for subclinical markers of renal dysfunction (albumin, alpha(1)-microglobulin and N-acetyl-beta-D-glucosaminidase). RESULTS: Data from 18 patients were analysed. Both groups demonstrated glomerular and proximal convoluted tubular dysfunction that was unaffected by steroid treatment. Steroid administration increased serum levels of urea and creatinine (both P < 0.001). The steroid group had increased interleukin 10 levels (P = 0.005 compared to controls). There were no differences between groups in overall surgical complications, length of intensive care unit (P = 0.821) and hospital (P = 0.719) stay, or 30-day mortality. CONCLUSION: Methylprednisolone administration altered the cytokine profile favourably but adversely affected postoperative renal function.

Measurement of urinary N-acetyl-b-D-glucosaminidase in adult patients with cystic fibrosis: before, during and after treatment with intravenous antibiotics.

BACKGROUND: Patients with cystic fibrosis (CF) are at high risk from the nephrotoxic effects of intravenous antibiotics due to repeated and prolonged courses of therapy. Routine methods of monitoring renal injury are insensitive. N-acetyl-b-d-glucosaminidase (NAG) is a lysosomal enzyme present in the renal proximal tubular cells, with increased excretion an indicator of renal tubular dysfunction. METHODS: Urinary NAG, creatinine, serum creatinine, electrolytes and BUN were measured on days 1, 14 and at the first out-patient visit following treatment with tobramycin or colistin. Urinary NAG levels were corrected for urinary creatinine and expressed as a NAG ratio. Patients who received>1 course of intravenous antibiotics during the study period were included in a separate analysis of the cumulative effect of treatment. RESULTS: 88 patients (44 female, 31 with CFRD) completed a single course of intravenous antibiotics. 71 patients had urinary NAG levels at follow-up. The median time to follow-up was 50 days. Serum electrolytes, creatinine and BUN were normal throughout. A 3.5-fold increase in urinary NAG excretion was observed between day 1 and 14 and 46% of patients had an elevated NAG level at follow-up. A highly significant difference in NAG excretion was observed on day 14 for tobramycin vs. colistin (median 2.24 vs. 0.98, p<0.001). A significant difference in NAG excretion was seen in patients with CFRD at all measured time points. Patients with CFRD had a significantly worse clinical status and had received more days of intravenous antibiotics over the previous 6 years. In 20 (80%) of 25 patients who received>1 course of treatment during the study period, baseline NAG levels were significantly higher in subsequent courses (p<0.001). There was a significant correlation between previous exposure to colistin and baseline NAG levels (r=0.389, p<0.001). CONCLUSIONS: Both tobramycin and colistin cause acute renal tubular injury with a significant rise in urinary NAG excretion. Patients with CFRD seem to be at greatest risk of renal tubular damage. Cumulative damage is evident with repeated dosing. Previous exposure to nephrotoxic antibiotics, especially colistin, is associated with elevated baseline NAG levels. We recommend that colistin is reserved for patients with resistant Pseudomonas aeruginosa or those who are intolerant to tobramycin. Serial longitudinal NAG measurements may be useful in patients with CF, especially those with CFRD, to identify patients at risk of developing renal disease.

Effect of perioperative steroids on renal function after liver transplantation.

Subclinical renal dysfunction is thought to occur as a systemic manifestation of ischaemia-reperfusion injury of other organs. Liver transplantation is associated with major ischaemia-reperfusion injury. Thirty-four patients undergoing elective liver transplantation were randomly allocated to receive either saline or 10 mg.kg(-1) methylprednisolone on induction of anaesthesia. Urine was taken for N-acetyl-beta-D-glucosaminidase, creatinine and other markers of tubular function. Serum chemistry was measured for 7 days. Creatinine concentration increased in the saline group but not in the methylprednisolone group (p < 0.0001), with the greatest difference on the third postoperative day (mean (SD) 164.8 (135.8) mumol.l(-1)vs 88.5 (39.4) mumol.l(-1), respectively). Similar changes were seen in postoperative alanine transferase (865 (739) U.l(-1)vs 517 (608) U.l(-1), respectively; p < 0.0001) on the second postoperative day. Both groups exhibited increases in markers of renal tubular dysfunction and of glomerular permeability. Patients in the saline group sustained more adverse events (8/17 (47%) vs 2/17 (12%); p = 0.02). The data confirm increased proximal tubular lysosomal turnover, consistent with an increased tubular protein load, following liver transplantation, and suggest that methylprednisolone protects against renal and hepatic dysfunction.

Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer.

Reduced expression of the adhesion molecule E-cadherin has been associated with increased invasiveness and poorer survival in patients with bladder cancer. We have examined soluble E-cadherin (sE-cadherin) and total protein concentrations in urine from patients with bladder cancer (n = 34), non-neoplastic benign urological diseases (n = 14) and healthy controls (n = 21) to determine their diagnostic and prognostic significance. Soluble E-cadherin concentrations of the cancer group were significantly higher (P < 0.001) than those of the controls but the benign group was not significantly different from either the cancer group or the controls. When sE-cadherin concentrations were adjusted for creatinine, similar but more statistically significant results were obtained and the benign group was significantly elevated compared with the controls (P < 0.01). No differences were apparent between the invasive (pT1-4) and non-invasive (pTa) cancers. Urinary total protein concentrations in the cancer group were significantly higher than the controls (P < 0.001) and the benign group (P < 0.05) although no difference was seen between the benign group and patients with non-invasive (pTa) cancer or between the benign group and controls. When expressed as the protein/creatinine index, results were similar but more statistically significant and a significant difference was seen between invasive and non-invasive cancers (P < 0.01). Only the protein/creatinine index correlated significantly with stage of the tumour (P < 0.01). It is concluded that urinary sE-cadherin measurements are of no greater value than urinary total protein.

Urine N-acetyl-beta-D-glucosaminidase--a marker of tubular damage?

BACKGROUND: Although an indicator of renal tubular dysfunction, an increased urinary N-acetyl-beta-D-glucosaminidase (NAG) activity might reflect increased lysosomal activity in renal tubular cells. METHODS: Puromycin aminonucleoside (PAN) was administered to Sprague Dawley rats to induce proteinuria. Total protein, albumin, NAG activity and protein electrophoretic pattern were assessed in daily urine samples for 33 days. The morphological appearance of the kidneys was examined on days three, four, six, eight and thirty three and the NAG isoenzyme patterns on days zero, four, eight and thirty three. RESULTS: Following intravenous PAN urine volume and urine NAG activity increased significantly by day two, but returned to normal by day four. After day four all treated animals exhibited a marked rise in urine albumin, total protein excretion and NAG activity. Electrophoresis showed a generalised increase in middle and high molecular weight urine proteins from day four onwards. Protein droplets first appeared prominent in tubular cells on day four. Peak urine NAG activity and a change in NAG isoenzyme pattern coincided with both the peak proteinuria and the reduction in intracellular protein and NAG droplets (day six onwards). CONCLUSIONS: This animal model demonstrates that an increase in lysosomal turnover and hence urine NAG activity, occurs when increased protein is presented to the tubular cells. Urine NAG activity is thus a measure of altered function in the renal tubules and not simply an indicator of damage.

Drugs of abuse in urine: some pitfalls in testing.

Drugs of abuse are usually detected in urine samples-drugs of abuse in urine (DAU). Whilst DAU testing may be required in the clinical situation, it is also a potential source of income from (e.g.) pre-employment medical examinations. DAU test results can, therefore, quite easily become the subject of legal debate. These points are discussed, along with an overview of the documentation procedures necessary should a laboratory decide to offer this service, and a brief survey of the screening and confirmatory testing procedures available.