The effect of soil texture on the degradation of textiles associated with buried bodies.

There are many factors which affect the rate of decomposition in a grave site including; the depth of burial, climatic conditions, physical conditions of the soil (e.g. texture, pH, moisture), and method of burial (e.g. clothing, wrappings). Clothing is often studied as a factor that can slow the rate of soft tissue decomposition. In contrast, the effect of soft tissue decomposition on the rate of textile degradation is usually reported as anecdotal evidence rather than being studied under controlled conditions. The majority of studies in this area have focused on the degradation of textiles buried directly in soil. The purpose of this study was to investigate the effect of soil texture on the degradation and/or preservation of textile materials associated with buried bodies. The study involved the burial of clothed domestic pig carcasses and control clothing in contrasting soil textures (silty clay loam, fine sand and fine sandy loam) at three field sites in southern Ontario, Canada. Graves were exhumed after 2, 12 and 14 months burial to observe the degree of degradation for both natural and synthetic textiles. Recovered textile samples were chemically analyzed using infrared (IR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) to investigate the lipid decomposition by-products retained in the textiles. The findings of this study demonstrate that natural textile in contact with a buried decomposing body will be preserved for longer periods of time when compared to the same textile buried directly in soil and not in contact with a body. The soil texture did not visually impact the degree of degradation or preservation. Furthermore, the natural-synthetic textile blend was resistant to degradation, regardless of soil texture, contact with the body or time since deposition. Chemical analysis of the textiles using GC-MS correctly identified a lipid degradation profile consistent with the degree of soft tissue decomposition. Such information may be important for estimating time since deposition in instances where only grave goods and associated materials are recovered from a burial site.

Multidimensional geriatric assessment in treatment decision in elderly cancer patients: 6-year experience in an outpatient geriatric oncology service.

This prospective cohort study of consecutive elderly cancer patients was undertaken to evaluate the role of the multidimensional geriatric assessment (MGA) as an aid in treatment decision-making. A total of 571 cancer patients (aged > or =70) were enrolled during 6-year (1999-2005). All underwent MGA as part of the first evaluation. In multivariate analysis, the probability of receiving active, instead of palliative, treatment was negatively associated with increasing age (odds ratio=0.69 every 5 years, p=0.005), living alone (OR=0.54, p=0.031), dependence in activities of daily living (ADL score >0, OR=0.41, p=0.003) and a low body-mass index (BMI) (OR=0.51, p=0.061); while a positive association emerged for instrumental activities of daily living (IADL) score (OR=1.12 per point, p=0.019). Our data suggest that MGA, in addition to age, is a useful tool in clinical practice for deciding cancer treatment in elderly patients, with a major independent role played by living alone, ADL, IADL and BMI.

Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF.

It is not known how different steroid-free immunosuppressive combinations affect renal graft survival and long-term kidney transplant function. Here we sought to compare the impact on graft survival and long-term graft function of two tacrolimus (Tac)-based, prednisone-free maintenance immunosuppressive protocols: Tac/Mycophenolate Mofetil (MMF) vs. Tac/Sirolimus (SRL). Renal transplant patients given induction therapy with IL2-RA and methylprednisolone on days 0, 1 and 2 post-transplant were prospectively randomized to two maintenance immunosuppressive regimens with Tac/MMF (n = 45) or Tac/SRL (n = 37). During the 3-year follow-up the following data were collected: patient survival, renal allograft survival, incidence of acute rejection and glomerular filtration rate (GFR) at different time-points post-transplant. Cumulative graft survival was significantly different in the two groups: one kidney loss in the Tac/MMF vs. six kidney losses in the Tac/SRL (log-rank test p = 0.04). GFR at different time-points post-transplant was consistently and statistically better in the Tac/MMF than in the Tac/SRL group. The slope of GFR decline per month was flatter in the Tac/MMF than in the Tac/SRL group. This study showed that renal graft survival and graft function were significantly lower in the combination of Tac/SRL than Tac/MMF.

Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial.

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

Myxobacteria isolated in Israel as potential source of new anti-infectives.

AIMS: To evaluate the patterns of the production of antimicrobial compounds by Israeli myxobacteria newly isolated from soil samples and barks by a battery of isolation and purification methods. METHODS AND RESULTS: A total of 100 myxobacteria belonging to five of the 12 described genera, were isolated from 48 soil and 45 tree bark samples collected in different areas inside the State of Israel. Four isolation methods based on the peculiar metabolic and cell cycle aspects of myxobacteria, were combined with purification procedures and optimization of cultivation conditions. Ninety-seven strains were fermented and screened for antimicrobial activities. Production of antimicrobial activities was detected in 62 isolates. More than 50% of the collection (54 strains) was able to inhibit Escherichia coli growth. CONCLUSIONS: The results of this study support the idea that myxobacterial strains can be isolated from particular habitats and then cultivated and screened for their capacity to produce secondary metabolites endowed with antibacterial and antifungal activities. Myxovirescin, a typical poliketide myxobacterial antibiotic, has been identified in one Israeli isolate. Althiomycin, a thiazolyl peptide, which inhibits prokaryotic protein synthesis, usually produced by actinomycetes, was detected in three strains selected in this study. SIGNIFICANCE AND IMPACT OF THE STUDY: The results confirm that myxobacteria are prolific producers of a variety of bioactive secondary metabolites including antibacterial and antifungal compounds, being their high frequency of anti-Gram-negative activities particularly appealing for the current anti-infective research. So far their screening has often been hampered because their isolation is time-consuming and are quite difficult to handle and cultivate. In this paper we demonstrate that a proper combination of isolation, purification and cultivation methods allow their pharmaceutical exploitation.

Nephrotoxic aspects of cyclosporine.

Over the last 20 years cyclosporine (CsA) has improved the survival of kidney, heart, and liver transplants. However, with increasing use, evidence has accumulated that CsA therapy carries a variety of side effects, the most important being renal toxicity. CsA can lead to a wide spectrum of renal function impairments, including a marked and rapidly reversible decrease in renal hemodynamics (acute CsA nephrotoxicity), and a chronic form of renal damage that potentially progress irreversibly to end-stage renal disease (chronic CsA nephrotoxicity). All these manifestations are the consequence of the drug toxic effects on renal vessels and the tubulointerstitium. A proper diagnosis of CsA toxicity at early stages, the combination of low CsA doses with non-nephrotoxic immunosuppressants, and the development of more feasible strategies to monitor daily CsA exposure may contribute to a better CsA management, improve quality of life of transplant recipients, and prolong graft survival.

Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients.

BACKGROUND: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is now routinely used as immunosuppressant in solid organ transplantation in a fixed daily dose regimen (2 g/d) in association with cyclosporine (CsA) and steroids. However, no correlation has been shown between fixed MMF dose and clinical outcome. METHODS: Here we examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring in 46 stable kidney transplant recipients. MPA plasma concentration profiles were measured by a reverse-phase high-performance liquid chromatography method 6-9 months after transplantation and related with routine laboratory analysis tests. Since MPA is extensively bound to serum albumin and only the free fraction is pharmacologically active, in a subgroup of 23 patients free plasma MPA was also determined. RESULTS: Despite a comparable MMF dose, a large interindividual variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.1-99.8 microg/mL. h) and in trough levels (range 0.24-7.04 microg/mL) was found. Patients with AUC >40 microg/mL. h showed a better (p<0.05) renal function than patients with lower AUC (creatinine clearance 85.7+/-23.2 versus 64.5+/-17.5 mL/min), despite no difference in CsA dose, CsA AUC and blood CsA trough level. The percentage of free plasma MPA but not total MPA correlated with the red blood cell and leukocyte count. CONCLUSIONS: Therapeutic MMF drug monitoring might contribute to a better management of kidney transplant recipient with the goal of optimizing drug dosing and limiting the risk of MMF-related toxicity.

Whole-blood calcineurin activity is not predicted by cyclosporine blood concentration in renal transplant recipients.

BACKGROUND: In transplant patients, current cyclosporine (CsA) dose monitoring with classic pharmacokinetics has demonstrated limitations. Evaluation of the activity of calcineurin (CN), the serine-threonine phosphatase enzyme target of CsA, has been proposed as a reliable way to optimize CsA dosing. METHODS: CN activity was measured in whole blood in an attempt to overcome the high variability of results obtained previously with peripheral blood mononuclear cells (PBMCs). We also explored, in vitro, a possible relationship between the CsA concentration and CN inhibition in whole blood. Finally, we assessed whether the CsA blood trough concentration correlates with whole-blood CN activity in kidney transplant recipients (n = 15) on maintenance immunosuppression with CsA. RESULTS: In 14 healthy individuals, less scattered CN activity values were documented in whole blood than in the PBMC fraction. Whole-blood CN activity was higher than the sum of the enzyme activity in each cell blood fraction. After ex vivo incubation of whole blood from healthy subjects (n = 5) with increasing concentrations of CsA (50-1000 microg/L for 1 h), a concentration-dependent inhibition of CN activity was found comparable to that in the PBMC fraction. Moreover, in 15 kidney transplant recipients, no relationship was found between CsA pharmacokinetic parameters and CN activity at time 0. However, a highly significant correlation was found between CN area under the CN activity-time curve, which represents the extent of the CN daily inhibition, and CN activity at time 0 (r = 0.79; P <0.01) and at 12 h postdosing (r = 0.96; P <0.01). CONCLUSIONS: Measuring CN activity in whole-blood samples is a reproducible method. In kidney transplant recipients, CsA trough concentrations do not predict baseline CN activity. Moreover, a single CN activity monitoring at baseline or at time 12 h post-CsA dosing may be a useful surrogate for the inhibition of this enzyme by CsA during 12 h.

Pharmacokinetic study of the new cyclosporine-A formulation (Neoral) in adult allogeneic bone marrow transplant recipients.

BACKGROUND AND OBJECTIVES: A major problem encountered during oral cyclosporin-A (CsA) administration to prevent acute graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) is its irregular pharmacokinetics. The aim of this study was to evaluate the pharmacokinetics of Neoral, a new water-free microemulsion formulation of CsA. DESIGN AND METHODS: Eighteen patients aged over 18 were enrolled into the study. When able to eat normally after allo-BMT, patients received CsA orally and after 4 days a 12-hour CsA pharmacokinetic profile was constructed. Three patients received Sandimmune 10 mg/kg/day, 5 patients received Neoral 7.5 mg/kg/day and 10 patients Neoral 5 mg/kg/day. CsA concentration was analyzed on whole blood by high-performance liquid chromatography (HPLC). RESULTS: Neoral showed concentration-time profiles characterized by a smooth and faster rise to the Cmax value compared to that produced by Sandimmune. The comparison between pharmacokinetic parameters obtained in patients receiving Neoral 5 mg/kg/day or 7.5 mg/kg/day showed a proportional increase of the AUC (4776+/-1084 vs. 7746+/-2006 ng/mL h) and C(max) (1027+/-203 vs. 1514+/-231 ng/mL). In all patients to whom 7.5 mg/kg/day of Neoral were given, C(trough) levels were always above the threshold of 200 ng/mL. INTERPRETATION AND CONCLUSIONS: Our data suggest that oral administration of Neoral 7.5 mg/kg/day early after allo-BMT may represent an appropriate dose resulting in adequate CsA C(trough) levels without significant renal toxicity.

Pretreatment blood pressure reliably predicts progression of chronic nephropathies. GISEN Group.

BACKGROUND: Random, nontimed blood pressure (BP) measurements in the outpatient clinic may fail to provide reliable information on actual daily BP control in renal patients on chronic antihypertensive therapy. METHODS: In a cohort of 163 patients with proteinuric chronic nephropathies followed prospectively with repeated BP and glomerular filtration rate (GFR) measurements, we compared baseline and follow-up pretreatment, morning ("trough," measured by standard procedures, and "0 minutes," measured by an automatic device) and post-treatment (120 minutes) measurements, with BP monitored up to 600 minutes after treatment administration. We then evaluated which BP value most reliably predicted GFR decline (delta GFR) and progression to end-stage renal failure (ESRF) over a median (interquartile range) follow-up of 20 (9 to 25) months. RESULTS: GFR decline was more reliably predicted by systolic as compared with diastolic BP and by pretreatment as compared to post-treatment BP, regardless of the timing and method of measurement, respectively. In particular, at the 120-minute baseline and follow-up measurements, systolic BP had no predictive value in patients with less severe renal insufficiency and baseline diastolic BP, regardless of the level of renal dysfunction. The BP predictive value was remarkably higher in ramipril than in conventionally treated patients. All follow-up-but no baseline-measurements reliably predicted the risk of ESRF in the entire study group. CONCLUSIONS: In patients with progressive chronic nephropathies, systolic BP and pretreatment morning BP measurements are the most reliable predictors of disease outcome and may serve to guide antihypertensive therapy in routine clinical activities and in prospective controlled trials, particularly in patients on angiotensin-converting enzyme inhibitor therapy. Reliability and relevance of single measurements taken at different times after treatment administration are questionable.

17beta-estradiol corrects hemostasis in uremic rats by limiting vascular expression of nitric oxide synthases.

Conjugated estrogens shorten the prolonged bleeding time in uremic patients and are similarly effective in a rat model of uremia. We have previously demonstrated that the shortening effect of a conjugated estrogen mixture or 17beta-estradiol on bleeding time was abolished by the nitric oxide (NO) precursor L-arginine, suggesting that the effect of these drugs on hemostasis in uremia might be mediated by changes in the NO synthetic pathway. The present study investigated the biochemical mechanism(s) by which conjugated estrogens limit the excessive formation of NO. 17beta-estradiol (0.6 mg/kg), given to rats made uremic by reduction of renal mass, significantly reduced bleeding time within 24 h and completely normalized plasma concentrations of the NO metabolites, nitrites and nitrates, and of NO synthase (NOS) catalytic activity, determined by NADPH-diaphorase staining in the thoracic aorta. Endothelial NOS (ecNOS) and inducible NOS (iNOS) immunoperoxidase staining in the endothelium of uremic aortas of untreated rats was significantly more intense than in control rats, while in uremic rats receiving 17beta-estradiol staining was comparable to controls. Thus 17beta-estradiol corrected the prolonged bleeding time of uremic rats and fully normalized the formation of NO by reducing the expression of ecNOS and iNOS in vascular endothelium. These results provide a possible biochemical explanation of the well-known effect of estrogens on primary hemostasis in uremia, in experimental animals and humans.

Nature and mediators of renal lesions in kidney transplant patients given cyclosporine for more than one year.

BACKGROUND: Cyclosporine (CSA) has improved patients and organ-graft survival rates, but its chronic nephrotoxicity is still an issue. Although prolonged vasoconstriction could contribute to chronic CsA tubulointerstitial changes by producing chronic ischemia, this relationship has been difficult to demonstrate thus far, and cellular origin and mediators of these structural alterations remain ill-defined. METHODS: As a part of a clinical trial in kidney transplant recipients on triple immunosuppressive therapy (CsA, azathioprine and steroid), which includes renal biopsy as "per protocol," 22 patients enrolled between 12 and 24 months posttransplantation underwent renal hemodynamic evaluation by measuring glomerular filtration rate and renal plasma flow by the plasma clearance of unlabeled iohexol and the renal clearance of para-aminohippuric acid, respectively. In parallel, the CsA pharmacokinetic profile was also determined. A week later, a protocol biopsy of kidney graft was performed. Light microscopy examination and localization of endothelin-1, RANTES, monocyte chemoattractant protein-1 gene expression by in situ hybridization in the graft specimens were evaluated and related to the pattern of histologic lesions. RESULTS: Ten out of 22 kidney transplant recipients who underwent the protocol biopsy had CsA nephrotoxicity, eight had chronic rejection, and four had no lesions at histological examination. The total daily exposure to CsA was higher in patients with CsA nephrotoxicity than in those with chronic rejection or no lesions at biopsy. Renal function was preserved in the CsA toxicity group as compared with the chronic rejection group, despite some degree of renal hypoperfusion. Tubular atrophy and striped interstitial fibrosis were found in all patients with light microscopical evidence of CsA nephrotoxicity, whereas glomerular and arteriolar lesions were less frequent. Intense staining for endothelin-1, RANTES, and monocyte chemoattractant protein-1 mRNAs selectively localized at tubular epithelial cells was found in biopsies taken from patients with CsA nephrotoxicity, but not in the chronic graft rejection group, whose tubuli had only minimal staining for RANTES mRNA on a few occasions. CONCLUSION: Long-term CsA administration to kidney allograft recipients leads to tubulointerstitial injury independently of its vascular effect. The possible contribution to the development of interstitial fibrosis of inflammatory and growth factors released by tubular cells in which CsA accumulates is proposed.

Application of newer clearance techniques for the determination of glomerular filtration rate.

Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of a filtration marker, such as inulin. This method, however, is not suitable for routine clinical practice. Labelled compounds as alternative filtration markers provide accurate and precise GFR measurement, but their use may be limited for safety reasons. Thus investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate and iohexol. Their renal clearance provides similar accuracy as inulin clearance in GFR estimation, but the need of urine collection again poses certain limitations to the procedure. Thus, plasma clearance of suitable exogenous markers, such X-ray contrast media, has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides precise information, but repeated sampling makes this method cumbersome. Abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve. The simplified method that uses a one-compartment model corrected by the Bröchner-Mortensen formula gives an excellent correlation with inulin clearance and is currently employed for measuring GFR in multi-centre clinical trials.

Abbreviated kinetic profiles in area-under-the-curve monitoring of cyclosporine therapy. Technical note.

BACKGROUND: The new microemulsion formulation of cyclosporine (CsA-ME) displays more consistent pharmacokinetic properties than the original formulation and may allow successful implementation of an abbreviated area-under-the-curve (AUC) strategy. METHODS: Here we compared two limited sampling strategies in order to define the one that best predicts AUC after CsA-ME in 51 renal transplant recipients with stable renal function. Pharmacokinetics were based on analysis of blood samples collected over 12 hours after drug administration by high-performance liquid chromatography (HPLC). Predicted AUC was estimated by using a three-point (0, 1 and 3 hr) or a two-point (2 and 6 hr or 0 and 2 hr) sampling strategy. RESULTS: A simplified strategy with three time points of blood collection at 0, 1, and 3 hours after CsA-ME allowed adequate and accurate prediction of the daily exposure to CsA. AUC prediction with two-point sampling at 2 and 6 hours was less good with a very large error in prediction (only 59% of the estimated AUC were within the accepted range). This limitation was even more evident when the 0 and 2 hour time points were examined, in which only 51% of AUC estimates were included in the accepted range of variation (-10 to 10%). CONCLUSIONS: A limited strategy of three-point sampling taken early after dosing allows an excellent and perfectly reliable prediction of the actual AUC.

How to convert from traditional cyclosporine to the microemulsion formulation in stable renal transplant patients?

How to convert from traditional cyclosporine (CsA) to the microemulsion formulation in stable renal transplant patients is still a matter of debate. The present study was designed to evaluate the effects of changeover from traditional Sandimmune to Neoral formulation at two dose-ratio conversions on CsA pharmacokinetics, safety and tolerability particularly in terms of renal function. Thirty outpatients regularly followed at our Clinical Research Center were randomized to 1:1 or 1:0.75 dose-ratio conversion and assigned to the two groups according to a comparable renal function and time post-transplant. Patients underwent CsA pharmacokinetic evaluation and renal function measurements (GFR and RPF) before, at day 15, and at month 6 after conversion to Neoral formulation. More consistent CsA concentration-time profiles with Neoral than traditional formulation were obtained at the two time points of evaluation after conversion. At 1:1 dose-ratio conversion an increased absorption rate, reflected by a shorter time to maximum blood CsA concentration (Tmax), and a greater bioavailability, as shown by an increase in the peak CsA concentration (Cmax) and the 12-h exposure to drug defined by the area under the time-concentration curve (AUC0-->12 h) was found 15 d and 6 months after conversion to Neoral formulation. A similar AUC as compared with traditional Sandimmune was observed in those patients randomized to receive a 25% lower dose of Neoral formulation. All of patients defined as 'low' absorbers became 'high' absorbers as early as 15 d after conversion to Neoral formulation at 1:1 or 0.75 dose-ratio regimen. Overall mean GFR was unchanged in both conversion regimens during the 6 months of follow-up. However, there was a tendency to lower GFR even in some patients randomized to 1:0.75 conversion but mostly in those with 1:1 conversion. A limited sampling strategy utilizing three blood samples (0, 1, 3 h post-dosing of Neoral formulation) provided an excellent correlation with actual drug exposure (r = 0.977). Enhanced CsA absorption with the microemulsion formulation results in increased drug exposure that may reduce GFR in some patients who undergo 1:1 dose-ratio conversion. The Neoral formulation that permits a more effective, consistent, and predictable absorption of CsA may represent a great advantage in order to prevent acute and possibly chronic rejections. Efforts have to be made to find optimal therapeutic range and dosing schedule for this new formulation, which may be facilitated by using the limited sampling approach to predict AUC after only three-point sampling.

Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy.

BACKGROUND: The Ramipril Efficacy In Nephropathy (REIN) study found that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, ramipril safely reduced the rate of decline of the glomerular filtration rate (GFR) and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF), as compared with placebo plus conventional antihypertensive drugs at the same level of blood pressure control. At the end of the core study patients continued on or shifted to ramipril and were formally enrolled into the REIN follow-up study. METHODS: 97 patients entered the follow-up study. Patients originally randomised to ramipril continued with the same daily dose (n=51), whereas those originally on placebo plus conventional antihypertensive drugs switched to ramipril after the first visit of the follow-up study (n=46). Ramipril (1.25 to 5.00 mg/day) and conventional antihypertensive therapy were targeted at achieving diastolic blood pressure under 90 mm Hg. The main efficacy variables were GFR decline and ESRF (need for dialysis). Analysis was by intention to treat. FINDINGS: During the follow-up study the mean rate of GFR decline per month decreased from 0.44 (SD 0.54) mL/min per 1.73 m2 in the core study to 0.10 (0.50) mL/min per 1.73 m2 in patients originally randomised to ramipril (p=0.017), and from 0.81 (1.12) to 0.14 (0.87) mL/min per 1.73 m2 in those originally randomised to placebo plus conventional antihypertensive therapy (p=0.017). At the final visit, mean absolute GFR values were 12 mL/min per 1.73 m2 higher (33% better) in patients randomised to ramipril than in those assigned placebo (n=26 and 17, respectively: 35.5 [19.0] vs 23.8 [9.4] mL/min per 1.73 m2, p=0.01). 19 of the patients originally on ramipril versus 35 switched from placebo to ramipril progressed to ESRF (p=0.027) during the whole observation period; of these, six (8%) versus 14 (16%) reached that endpoint during the follow-up study; and the risk ratios were 1.86 (95% CI 1.07-3.26) over the whole observation period and 2.95 (1.13-7.68) during follow-up. Beyond follow-up at month 36, the incidence of ESRF was zero in patients originally randomised to ramipril but 30% in patients on placebo plus conventional antihypertensive therapy. INTERPRETATION: In patients with chronic nephropathy and high risk of rapid progression to ESRF, ramipril reversed the tendency of GFR to decline with time. Moreover, a treatment period of sufficient duration (> or =36 months) eliminated the need for dialysis. Even patients previously treated with antihypertensive drugs other than angiotensin-converting-enzyme inhibitors benefited from shifting to ramipril.

Effect of acetate, bicarbonate dialysis, and acetate-free biofiltration on nitric oxide synthesis: implications for dialysis hypotension.

The effect of acetate dialysis (AD), bicarbonate dialysis (BD), and acetate-free biofiltration (AFB) on nitric oxide (NO) synthesis and the implications for dialysis hypotension was studied. The finding that uremic plasma is a potent inducer of NO synthesis by endothelial cells in vitro suggested that the cardiovascular instability of dialysis patients might result from excessive NO formation. Cardiovascular instability is more frequent in patients undergoing AD than BD. To see whether these differences were attributable to NO, we studied the NO synthetic pathway ex vivo in patients undergoing different dialysis procedures. Five patients were treated, in a random order, with AD, BD, and AFB, a technique using a buffer-free dialysate and postdilution of a sterile bicarbonate solution. Each type of dialysis was used for 1 week, comprising three dialysis sessions. A polyacrylonitrile dialyzer was used for all three methods. Before and after the third dialysis, plasma was collected, added to [3H]L-arginine, and incubated with human umbilical vein endothelial cells (HUVECs) for 24 hours. NO synthesis was evaluated as [3H]L-citrulline formation. Plasma concentrations of interleukin-1beta (IL-1beta), a potent inducer of inducible NO synthase (iNOS) in endothelial cells, were also measured. Plasma collected from patients after AD stimulated endothelial NO synthesis more than plasma from the same patients before the dialysis session (pre-AD, 0.173+/-0.028 nmol/10(5) cells v post-AD, 0.280+/-0.093 nmol/10(5) cells; P < 0.05). A slight, although not significant, increase was also observed when HUVECs were incubated with plasma drawn after BD (pre-BD, 0.151+/-0.014 nmol/10(5) cells; post-BD, 0.230+/-0.055 nmol/10(5) cells). AFB did not aggravate the stimulatory effect of uremic plasma on endothelial NO synthesis (pre-AFB, 0.184+/-0.038 nmol/10(5) cells; post-AFB, 0.189+/-0.040 nmol/10(5) cells). Plasma IL-1beta was greater (P < 0.01) after AD than after BD and AFB (post-AD, 0.234+/-0.028 pg/mL; post-BD, 0.124+/-0.019 pg/mL; post-AFB, 0.120+/-0.013 pg/mL). With AD, there was a greater intradialytic decrease in systolic blood pressure than with BD or AFB. Weight and blood volume loss and sodium balance were similar in AD, BD, and AFB. These data were consistent with the possibility that NO and cytokines, released in excessive amounts during AD, may contribute to hemodynamic instability.