Randomized controlled trial: lisinopril reduces proteinuria, ammonia, and renal polypeptide tubular catabolism in patients with chronic allograft nephropathy.

BACKGROUND: Angiotensin-converting enzyme inhibitors in native nephropathies reduce proteinuria and delay progression to renal failure. Data in renal transplantation remain limited. A negative effect on glomerular filtration rate was concluded in a recent systematic review. METHODS: In this novel randomized controlled trial, 47 patients with chronic allograft nephropathy, severe renal impairment, and more than or equal to 1 g/24 hr proteinuria were randomized to lisinopril (group A) or other hypotensives (group B) for 1 year. Sodium bicarbonate was given to all patients to treat metabolic acidosis prophylactically (acidosis increases significantly with lisinopril). The annual rate of decline of graft function was measured isotopically (primary outcome) and 24 hr proteinuria, genotyping, radiolabeled polypeptide aprotinin proximal tubular catabolic studies (in group A only) as secondary outcome measurements were undertaken. RESULTS: At baseline, groups were comparable except for greater proteinuria in group A. After 1 year, the rate of decline of graft function and graft survival were comparable in both groups. Proteinuria decreased significantly in group A patients only. Lisinopril also significantly reduced radiolabeled aprotinin uptake and metabolism, plasma aldosterone, and ammonia excretion. Plasma potassium, bicarbonate, and mean arterial pressures were comparable in both groups. Patients with more than or equal to 30% reduction in proteinuria had a significant association with rs699 polymorphism in the angiotensinogen gene. CONCLUSIONS: The rate of decline of renal graft function in patients with chronic allograft nephropathy was not adversely affected by lisinopril therapy given for 1 year. Lisinopril significantly reduced proteinuria, renal proximal tubular polypeptide catabolism, plasma aldosterone, and ammonia excretion suggesting relative preservation of graft function. Treating metabolic acidosis allowed safe and prolonged use of angiotensinogen-converting enzyme inhibitors.

Is Routine Spiral CT-Chest Justified in Evaluation of the Major Blunt Trauma Patients?

STUDY: New generation spiral CT scanners permit multiple consecutive CT examinations on the same trauma patient in a short period of time. The purpose of this study was to evaluate the diagnostic role and therapeutic impact of routine spiral CT chest in multiply injured patients or patients with a suspicious mechanism of injury. PATIENTS AND METHODS: This prospective study included 443 patients with blunt chest trauma. All patients underwent a spiral CT chest as part of their routine evaluation. Radiological interpretation of chest x-rays, CT scan findings, and changes in management plan guided by these findings were recorded. RESULTS: The mechanism of injury was road traffic accidents in 422 patients (95.26%). Out of the 167 patients with normal chest radiograph, 136 (81.43%) were found to have an abnormality on chest CT. The management was changed in the form of additional investigations or unplanned intervention in 92 patients (20.76%). Additional investigations included transoesophageal echocardiography (n = 7), bronchoscopy (n = 13), transfer to higher center for aortography (n = 2). Intercostal tubes (n = 55), thoracotomies (n = 4), fixation of sternal fracture (n = 9), laparotomy (n = 1) and spinalfixation (n = 1) were performed following the CT scan. CONCLUSION: Although the incidence of significant injuries identified by the chest CT scan was low, it did prompt immediate intervention in a significant number of patients; some of them had potentially life-threatening injuries. Routine use of CT scanning is warranted in early evaluation of polytrauma patients or patients with severe blunt chest trauma.

Clinical outcome of cadaveric renal allografts contaminated before transplantation.

This analysis was performed to define the incidence of pretransplant microbial contamination of donor kidneys, and to assess the resultant morbidity including infections requiring therapy, and graft loss. Case records of all 638 renal allograft recipients patients transplanted in our centre during the period June 1990 to October 2000 were studied. All the recipients were given a single dose of intravenous antibiotics at the time of induction of anaesthesia. A total of 775 microbiology reports on perfusion fluid, kidney swabs and ureteric tissue were retrieved. Fifty-eight of 638 (9.1%) patients were transplanted with a graft that showed preoperative contamination. 18 of these 58 patients (31%) subsequently required antibiotic treatment. Thirty of 32 patients who received kidney contaminated with skin flora had a benign course (i.e. no unexplained, no positive blood cultures or graft infection). By contrast, seven of nine recipients with grafts whose perfusion fluid yielded lactose fermenting coliforms (LFCs) required antibiotics and three of nine of them suffered graft loss as a result. Two of these patients had bacteraemia caused by LFC, and one died. Three of five patients with positive cultures due to yeast required treatment with antifungals. None of the four patients who had graft contaminated by Staphylococcus aureus became infected. One-year 49/58 (85%) of these patients survived with functioning graft. Overall 1-year patient survival was 53/55 (92%). These data suggest that contamination of renal allografts by LFCs or yeasts need to be treated preemptively before the onset of clinical manifestations. By contrast, contamination with skin contaminants does not pose a risk to the graft.

Multicenter, randomized study of the effectiveness of basiliximab in avoiding addition of steroids to cyclosporine a monotherapy in renal transplant recipients.

BACKGROUND: Steroid therapy is associated with an increased risk of cardiovascular events and well-documented adverse effects, but two thirds of patients initiated on monotherapy with cyclosporine A (CsA) microemulsion require addition of steroids. METHODS: In this 12-month randomized, double-blind, multicenter study, 108 renal transplant recipients were randomized and received basiliximab (n=52) or placebo (n=56) to assess whether basiliximab reduces the need for addition of steroids or other adjunctive immunosuppressive drugs to CsA monotherapy. RESULTS: The primary endpoint of the study (requirement for additional immunosuppression at 12 months posttransplant) occurred significantly less frequently with basiliximab (54%) than placebo (73%) (P=0.046). By the end of the study, 25% of basiliximab-treated patients were receiving maintenance steroids versus 61% of placebo-treated patients (P=0.0006). During the trial, 33% of basiliximab-treated patients received oral steroids at some time compared with 61% of placebo-treated patients (P=0.004). The proportion of patients experiencing biopsy-proven rejection was not significantly different between the basiliximab (29%) and placebo (43%) groups (P=0.16). Median serum creatinine at 12 months was 141 mumol/L with basiliximab and 164 mumol/L with placebo (not significant). One-year graft and patient survivals were 88% and 98% for basiliximab and 88% and 96% for placebo (not significant), respectively. Adverse events were similar in the basiliximab and placebo treatment groups. CONCLUSIONS: These findings demonstrate that the addition of basiliximab significantly reduces the need to modify the initial treatment regimen in patients scheduled to receive steroid-free CsA therapy, suggesting that basiliximab induction may be useful as a strategy in other steroid-avoidance regimens.

Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression.

BACKGROUND: Cyclosporine (CsA) is a substrate for the MDR-1 gene product P-glycoprotein (P-gp). CsA efficacy may be modulated by lymphocyte P-gp expression levels. In this study, CsA inhibition of lymphocyte proliferation in whole-blood cultures ex vivo has been related to (1) lymphocyte P-gp expression and (2) the C3435T polymorphism in the MDR-1 gene, which has been reported to alter P-gp function. METHODS: In 30 renal-transplant recipients taking CsA monotherapy, P-gp expression was measured by flow cytometry. Whole-blood samples were stimulated with purified protein derivative (PPD) and phytohemagglutinin (PHA). CsA resistance ex vivo was defined as less than 10% reduction in proliferation with either PPD or PHA at 2 hours compared with 0 hours. RESULTS: CsA resistance was associated with greater P-gp expression using either PPD (median expression, resistant 1.89 vs. sensitive 0.96, P =0.02) or PHA (1.66 vs. 0.96, respectively, P =0.02). Whole-blood CsA levels in resistant and sensitive patients were similar. The C3435T polymorphism did not affect inhibition of proliferation by CsA (P >0.05 for all between genotype group comparisons). CONCLUSIONS: Our results indicate that lymphocyte P-gp expression determines the degree of inhibition of proliferation by CsA ex vivo; whether this also affects CsA effectiveness in vivo and therefore graft survival requires further study.

Utility of serial Doppler ultrasound scans for the diagnosis of acute rejection in renal allografts.

This study aims to explore the utility of serial duplex scanning and to compare its results with those of single time-point scans of renal allografts in the diagnosis of acute rejection (AR). A retrospective analysis of 6017 serial duplex scans (mean: 9.8 scans per patient, 5.7 of which were done during the first 10 days) was performed in 614 patients with 462 episodes of AR from 1992-2000. Even in the absence of AR (n=278), there were day-to-day fluctuations in pulsatility index (PI) and resistive index (RI). An increase of >10% in intra-renal indices was noted 0.95 days (mean) before the commencement of treatment for AR (SD 1.3, range 1-6 days). In patients with acute tubular necrosis (ATN), who have high base line indices, sensitivity of single value of PI and RI was 58% (cut-off level 1.8) and 68% (cut-off level 0.8), with specificity of 66% and 56%, respectively. By contrast, a >10% increase over the previous 'best' in PI and RI had a sensitivity of 78% and 60% respectively, and a specificity of 78% and 90%, respectively. Reversal of flow during diastole (n=50) was found to be associated with 22% graft loss within 3 months of transplantation. We can conclude that a considerable overlap between the indices of patients with AR and those with ATN greatly limits the diagnostic yield of duplex scanning. Nonetheless, serial scanning of renal allografts is more likely to herald the need for biopsy in the diagnosis of AR than one-time scanning.