Pharmacokinetics of oxycodone/naloxone and its metabolites in patients with end-stage renal disease during and between haemodialysis sessions.

BACKGROUND: The pharmacokinetics of oxycodone in patients with end-stage renal disease (ESRD) requiring haemodialysis are largely unknown. Therefore, we investigated the pharmacokinetics of oxycodone/naloxone prolonged release and their metabolites in patients with ESRD during and between haemodialysis sessions. METHODS: Single doses of oxycodone/naloxone (5/2.5 or 10/5 mg) were administered in nine patients with ESRD using a cross-over design on the day of dialysis and on a day between dialysis sessions. Plasma, dialysate and urine concentrations of oxycodone, naloxone and their metabolites were determined up to 48 h post-dosing using a liquid chromatography-tandem mass spectrometry system. RESULTS: Haemodialysis performed 6-10 h after dosing removed ∼10% of the administered dose of oxycodone predominantly as unconjugated oxycodone and noroxycodone or conjugated oxymorphone and noroxymorphone. The haemodialysis clearance of oxycodone based on its recovery in dialysate was (mean ± SD) 8.4 ± 2.1 L/h. The geometric mean (coefficient of variation) plasma elimination half-life of oxycodone during the 4-h haemodialysis period was 3.9 h (39%) which was significantly shorter than the 5.7 h (22%) without haemodialysis. Plasma levels of the active metabolite oxymorphone in its unconjugated form were very low. CONCLUSIONS: Oxycodone is removed during haemodialysis. The pharmacokinetics including the relatively short half-life of oxycodone in patients with ESRD with or without haemodialysis and the absence of unconjugated active metabolites indicate that oxycodone can be used at usual doses in patients requiring dialysis.

Proenkephalin for the early detection of acute kidney injury in hospitalized patients with chronic kidney disease.

BACKGROUND: The early detection of acute kidney injury (AKI) in patients with chronic kidney disease (CKD) is an unmet clinical need. Proenkephalin (PENK) might improve the early detection of AKI. METHODS: One hundred and eleven hospitalized CKD patients undergoing radiographic contrast procedures were enrolled. PENK was measured in a blinded fashion at baseline (before contrast media administration) and on day 1 (after contrast media administration). The potential of PENK levels to predict contrast-induced AKI was the primary endpoint. RESULTS: Baseline creatinine and baseline PENK were similar in AKI and no-AKI patients. In AKI patients, day 1 PENK (198 pmol/L vs 121 pmol/L, P < 0.01) was significantly higher compared to no-AKI patients. The area under the curve (AUC) for the prediction of AKI by day 1 PENK was 0.79, 95% CI: 0.70-0.87, similar to serum creatinine: 0.78, 95% CI: 0.61-0.95. Delta PENK was significantly higher in AKI compared to no-AKI patients (53 pmol/L vs 1 pmol/L, P < 0.01). The AUC for the prediction of AKI by delta PENK was high (0.92, 95%CI 0.82-1.00) and remained high for creatinine-blind AKI (0.94, 95% CI: 0.87-0.97). CONCLUSION: Delta PENK levels improve the early detection of contrast-induced AKI in CKD patients over serial creatinine sampling. Delta PENK accelerates the detection of creatinine-blind AKI by 24 hours.

Rapidly progressive lupus nephritis with extremely high levels of antineutrophil cytoplasmic antibodies.

A 43-year-old woman, with a 3-month history of fatigue, anaemia and swollen lymph nodes, underwent biopsy of a lymph node, which revealed reactive lymphadenopathy. Due to an increased serum creatinine concentration and severe proteinuria, a kidney biopsy was performed, which revealed diffuse, segmental, proliferative, immune-complex glomerulonephritis with crescents. Electron microscopy showed tubulo-reticular structures within one endothelial cell. These were a typical clinical presentation and compatible histopathological findings for systemic lupus erythematosus; however, the anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) level was extraordinarily high. In spite of treatment with intravenous cyclophosphamide and methylprednisolone pulse therapy, the patient's kidney function declined. Starting plasma exchange improved her renal function and removed MPO-ANCAs, which were suspected to play the major role in the pathogenesis of glomerulonephritis. These findings indicate that in addition to lupus nephritis, MPO-ANCAs may be involved in the pathogenesis of glomerulonephritis and that the coincidence of systemic lupus erythematosus and ANCA may be responsible for the severe clinical course in our patient.

Recurrent bone fractures due to tenofovir-induced renal phosphate wasting.

A 42-y-old HIV-infected man suffered from several stress fractures due to tenofovir-induced proximal tubular injury. Laboratory examination revealed hypophosphatemia due to renal phosphate wasting. Therefore, more attention has to be paid to the monitoring of serum phosphate and alkaline phosphatase levels, since tenofovir-related nephrotoxicity increases the risk of osteomalacia.

Outcome of fibrillary glomerulonephritis.

QUESTIONS UNDER STUDY: We assessed the long-term follow up of all the patients with fibrillary glomerulonephritis diagnosed since 1992 at our centre of reference for renal pathology in Basel. METHODS: We performed a retrospective surveillance study with mail questionnaire based follow-up of all patients with the diagnosis of fibrillary glomerulonephritis found in the database of the department of renal pathology in Basel from 1992 to 2007. The outcome was assessed in terms of endstage renal disease (ESRD), death, reduction of proteinuria and improvement of estimated glomerular filtration rate (eGFR). RESULTS: We obtained sufficient follow up data from 16 out of 20 identified patients. The mean follow up time was 35 months (1-115.1). Six patients died (37.5%), three without having ESRD. Six patients (37.5%) reached ESRD, five of them went on hemodialysis. Thirteen patients (81.3%) received an immunosuppressive therapy with steroids, five of them in combination with cyclophosphamide. The group without immunosuppressive therapy was too small to compare the two groups. In relation to the histological pattern membranous glomerulonephritis (MGN) had a better outcome as compared to the other histological patterns. CONCLUSIONS: FGN is a heterogeneous disease associated with significant risk of ESRD and mortality. The histological type of the glomerulonephritis may influence the course of the disease.

Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: a randomized controlled trial.

AIMS: The most effective regimen for the prevention of contrast-induced nephropathy (CIN) remains uncertain. Our purpose was to compare two regimens of sodium bicarbonate with 24 h sodium chloride 0.9% infusion in the prevention of CIN. METHODS AND RESULTS: We performed a prospective, randomized trial between March 2005 and December 2009, including 258 consecutive patients with renal insufficiency undergoing intravascular contrast procedures. Patients were randomized to receive intravenous volume supplementation with either (A) sodium chloride 0.9% 1 mL/kg/h for at least 12h prior and after the procedure or (B) sodium bicarbonate (166 mEq/L) 3 mL/kg for 1 h before and 1 mL/kg/h for 6 h after the procedure or (C) sodium bicarbonate (166 mEq/L) 3 mL/kg over 20 min before the procedure plus sodium bicarbonate orally (500 mg per 10 kg). The primary endpoint was the change in estimated glomerular filtration rate (eGFR) within 48 h after contrast. Secondary endpoints included the development of CIN. The maximum change in eGFR was significantly greater in Group B compared with Group A {mean difference -3.9 [95% confidence interval (CI), -6.8 to -1] mL/min/1.73 m2, P = 0.009} and similar between groups C and B [mean difference 1.3 (95% CI, -1.7-4.3) mL/min/1.73 m(2), P = 0.39]. The incidence of CIN was significantly lower in Group A (1%) vs. Group B (9%, P = 0.02) and similar between Groups B and C (10%, P = 0.9). CONCLUSION: Volume supplementation with 24 h sodium chloride 0.9% is superior to sodium bicarbonate for the prevention of CIN. A short-term regimen with sodium bicarbonate is non-inferior to a 7 h regimen. ClinicalTrials.gov Identifier: NCT00130598.

Increasing B-type natriuretic peptide levels predict mortality in unselected haemodialysis patients.

AIMS: Cardiac disease is the major cause of death in patients undergoing chronic haemodialysis. Recent studies have found that B-type natriuretic peptide (BNP) levels accurately reflect the cardiovascular burden of dialysis patients. However, the prognostic potential of BNP measurements in dialysis patients remains unknown. METHODS AND RESULTS: The study included 113 chronic dialysis patients who were prospectively followed up. Levels of BNP were measured at baseline and every 6 months thereafter. The potential of baseline BNP and annual BNP changes to predict all-cause and cardiac mortality were assessed as endpoints. Median follow-up was 735 (354-1459) days; 35 (31%) patients died, 17 (15%) of them from cardiac causes. Baseline BNP levels were similar among survivors and non-survivors, and failed to predict all-cause and cardiac death. Cardiac death was preceded by a marked increase in BNP levels. In survivors BNP levels remained stable [median change: +175% (+20-+384%) vs. -14% (-35-+35%) over the 18 months preceding either death or the end of follow-up, P< 0.001]. Hence, annual BNP changes adequately predicted all-cause and cardiac death in the subsequent year {AUC(all-cause) = 0.70 [SD 0.05, 95% CI (0.60-0.81)]; AUC(cardiac) = 0.82 [SD 0.04, 95%CI (0.73-0.90)]}. A BNP increase of 40% provided the best cut-off level. Cox regression analysis confirmed that annual increases over 40% were associated with a seven-fold increased risk for all-cause and cardiac death. CONCLUSIONS: Annual BNP increases above 40% predicted all-cause and cardiac death in the subsequent year. Hence, serially measuring BNP levels may present a novel tool for risk stratification and treatment guidance of end-stage renal disease patients on chronic dialysis.