Geriatric Assessment and the Relation with Mortality and Hospitalizations in Older Patients Starting Dialysis.

BACKGROUND AND OBJECTIVES: A geriatric assessment (GA) is a structural method for identifying frail patients. The relation of GA findings and risk of death in end-stage kidney disease (ESKD) is not known. The objective of the GA in OLder patients starting Dialysis Study was to assess the association of GA at dialysis initiation with early mortality and hospitalization. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients ≥65 years old were included just prior to dialysis initiation. All participants underwent a GA, including assessment of (instrumental) activities of daily living (ADL), mobility, cognition, mood, nutrition, and comorbidity. In addition, a frailty screening (Fried Frailty Index, [FFI]) was applied. Outcome measures were 6- and 12-month mortality, and 6-month hospitalization. Associations with mortality were assessed with cox-regression adjusting for age, sex, comorbidity burden, smoking, residual kidney function and dialysis modality. Associations with hospitalization were assessed with logistic regression, adjusting for relevant confounders. RESULTS: In all, 192 patients were included, mean age 75 ± 7 years, of whom 48% had ≥3 geriatric impairments and were considered frail. The FFI screening resulted in 46% frail patients. Mortality rate was 8 and 15% at 6- and 12-months after enrolment, and transplantation rate was 2 and 4% respectively. Twelve-month mortality risk was higher in patients with ≥3 impairments (hazard ratio [HR] 2.97 [95% CI 1.19-7.45]) compared to less impaired patients. FFI frail patients had a higher risk of 12-month mortality (HR 7.22 [95% CI 2.47-21.13]) and hospitalization (OR 1.93 [95% CI 1.00-3.72]) compared to fit patients. Malnutrition was associated with 12-month mortality, while impaired ADL and depressive symptoms were associated with 12-month mortality and hospitalization. CONCLUSIONS: Frailty as assessed by a GA is related to mortality in elderly patients with ESKD. Individual components of the GA are related to both mortality and hospitalization. As the GA allows for distinguishing between frail and fit patients initiating dialysis, it is potentially of added value in the decision-making process concerning dialysis initiation.

Variable workup calls for guideline development for type 2A hereditary haemochromatosis.

BACKGROUND: Type 2A hereditary haemochromatosis (type 2A HH) is a rare iron-loading disorder caused by mutations in the HFE2 gene, which encodes the HJV protein. We present characteristics, treatment and follow-up of subjects diagnosed with type 2A HH in the Netherlands to increase awareness of the disease and its treatment, and to define knowledge gaps. METHODS: We collected clinical, biochemical and genetic data from seven patients (two female; five probands) from six families genetically diagnosed with type 2A HH at the Expertise Center for Iron Disorders, Radboud University Medical Centre between 2006 and 2016. RESULTS: The five probands presented with heterogeneous complaints between the ages of 19 and 39. One of two patients with delayed clinical diagnosis developed hypogonadism and Y. enterocolitica sepsis. Diagnostic workup and follow-up varied. When assessed, elevated transferrin saturation (79-98%), ferritin (1400-6200 µg/l) and severely elevated liver iron levels were found, and in all subjects, phlebotomies were initiated. One subject was switched to erythrocytapheresis. Target ferritin levels varied. Despite long-term iron depletion, two subjects developed clinical complications. Sanger sequencing revealed two pathogenic HFE2 variants (homozygous or compound heterozygous) for the five families of Dutch descent and one new pathogenic variant in the family of non-Dutch descent. CONCLUSION: Three genetic variants caused type 2A HH in six families. Clinical diagnosis was delayed in two subjects. We observed variance in presentation, workup, follow-up and treatment. We found new complications in long-term iron-depleted patients. We recommend research and guidelines for optimal workup, follow-up and treatment of type 2A HH.

Effectiveness of a third tumor necrosis factor-α-blocking agent compared with rituximab after failure of 2 TNF-blocking agents in rheumatoid arthritis.

OBJECTIVE: To compare the effectiveness of a third tumor necrosis factor-α (TNF-α)-blocking agent with rituximab after failure of 2 TNF-blocking agents in patients with rheumatoid arthritis (RA) in daily clinical practice. METHODS: Patients receiving a third TNF-blocking agent or rituximab after failure of 2 TNF-blocking agents were selected from a Dutch biologic registry. The primary outcome was the results from the Disease Activity Score of 28 joints (DAS28) over the first 12 months after start of the third biologic using mixed-model analyses. Secondary outcomes included the course of the Health Assessment Questionnaire (HAQ) and the separate components of the DAS28 over the first 12 months and the change from baseline in DAS28 and HAQ at 3 and 6 months. RESULTS: The overall course of the DAS28 over the first 12 months was significantly better for rituximab (p = 0.0044), as also observed for the HAQ, although the latter results were not statistically significant (p = 0.0537). The erythrocyte sedimentation rates, C-reactive protein, and swollen joint counts showed a better course for rituximab (p = 0.0008, p = 0.0287, p = 0.0547, respectively), but not the tender joint counts or visual analog scale for general health. DAS28 decreased significantly in both groups at 3 and 6 months (p ≤ 0.024), but the change in HAQ was significant for rituximab only at 3 months (p = 0.009). CONCLUSION: During the first 12 months of therapy, a larger improvement in disease activity and a trend toward a larger decrease in functional disability was observed in patients receiving rituximab. Switching to a biologic with another mechanism of action might be more effective after failure of 2 TNF-blocking agents in RA.

Patients' representations of their end-stage renal disease: relation with mortality.

BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with type 2 diabetes -- CORALL study.

OBJECTIVES: To compare the efficacy of the newest cholesterol-lowering drug, rosuvastatin (RSV) with atorvastatin (ATV) in subjects with type 2 diabetes. DESIGN: A 24-week, open-label, randomized, parallel-group, phase IIIb, multicentre study. SETTING: Diabetes outpatient clinics of 26 hospitals in The Netherlands. SUBJECTS: A total of 263 patients with type 2 diabetes treated with oral agents or insulin, age (mean +/- SD) 60 +/- 10 years, body mass index (BMI) 31.4 +/- 6.1 kg m(-2), 46% males. INTERVENTION: After a 6-week dietary lead-in period, patients were randomized to RSV (n = 131) or ATV (n = 132) treatment in a dose escalation scheme (RSV: 10, 20 and 40 mg or ATV: 20, 40 and 80 mg for 6 weeks each sequentially). MAIN OUTCOME MEASURES: Primary outcome was the change in apolipoprotein B (apoB) and apoB/apolipoprotein A1 (apoA1) ratio, which has been suggested a better predictor for cardiovascular events than total (TC) or low-density lipoprotein cholesterol (LDL-C). Secondary outcomes were the changes in other lipid parameters. RESULTS: Baseline LDL-C in the RSV and ATV groups was 4.23 +/- 0.98 mmol L(-1) and 4.43 +/-0.99 mmol L(-1), whilst apoB/apoA1 was 0.86 +/-0.22 and 0.92 +/- 0.35, respectively. A greater reduction in apoB/apoA1 was seen with RSV (-34.9%, -39.2% and -40.5%) than with ATV (-32.4%, -34.7% and -35.8%, P < 0.05 at weeks 12 and 18). Significantly greater reductions in LDL-C were also seen with RSV (-45.9%, -50.6% and -53.6%) than with ATV (-41.3%, -45.6% and -47.8%, all P < 0.05). The American Diabetes Association (ADA) LDL-C goal of < 2.6 mmol L(-1) was reached by 82%, 84% and 92% of patients with RSV and 74%, 79% and 81% with ATV. Triglyceride reductions ranged from 16 to 24% and were not different between treatments. Both treatments were well-tolerated: nine patients in the RSV and 11 in the ATV group withdrew from treatment because of adverse events after randomization. CONCLUSION: In subjects with type 2 diabetes, greater improvements of apoB/apoA1 and across the lipid profile were observed with RSV compared with ATV.

Catheter replacement in continuous arteriovenous hemodiafiltration: the balance between infectious and mechanical complications.

OBJECTIVE: To assess the optimal moment of central vascular catheter replacement balancing infectious and mechanical complications in continuous renal replacement therapies in critically ill patients with acute renal failure. METHODS: Prospective sequential trial with historical controls to compare liberal catheter replacement when clinically indicated with routine catheter replacement every 5 days in consecutive patients treated by continuous arteriovenous hemodiafiltration in a level I secondary referral intensive care unit of a university-affiliated teaching hospital. Intention-to-treat analysis. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients underwent catheter replacement when clinically indicated (group II), and 21 patients served as historical controls (group I). The groups were comparable for sex, age, Acute Physiology and Chronic Health Evaluation II scores, comorbidity, and creatinin and urea levels at the start of continuous arteriovenous hemodiafiltration. In group I, 71 catheters were used for 346 treatment days, and in group II, 68 catheters were used for 495 treatment days. The mean duration of catheterization was 4.9 +/- 2.0 days vs. 7.3 +/- 4.5 days, respectively (Student's t-test p <.001). There was no significant difference between the incidence of colonization of catheters (46.8% in group I vs. 39.1% in group II; chi-square p =.35) In group I, bacteremia and catheter sepsis occurred in two patients, whereas this did not occur in group II. The occurrence of mechanical complications was comparable in both groups (15.5% in group I vs. 19.1% in group II). There were significantly more mechanical complications with arterial vs. venous catheters (17 vs. 7; chi-square p =.027). CONCLUSION: When catheters were changed as clinically indicated, they remained significantly longer in situ vs. being replaced routinely every 5 days; infectious and mechanical complications were comparable. The incidence of catheter sepsis was low (2.2%), and no prosthesis infection occurred. Catheter replacement when clinically indicated seems to be as safe as routine replacement every 5 days.

Simulation study of the intercompartmental fluid shifts during hemodialysis.

Hypotension is the most frequent complication during hemodialysis. An important cause of hypotension is a decrease in the intravascular volume. In addition, a decrease in plasma osmolality may be a contributing factor. Modeling of sodium and ultrafiltration (UF) may help in the understanding of underlying relationships. We therefore simulated, in a mathematical model, the intercompartmental fluid shifts during standard hemodialysis (SHD), diffusive hemodialysis (DHD), and isolated ultrafiltration (IU). We analyzed the relative theoretical effect of hydration status, dialysate sodium concentration, the initial plasma concentrations of sodium and urea, and tissue permeation to solutes on the magnitude and direction of intracellular and intravascular volume changes. This theoretical analysis shows that the transcellular fluid shifts taking place during hemodialysis treatment are, to a great part, due to inhomogeneous distribution of regional blood flow and tissue fluid volumes. During hemodialysis treatment, the cellular fluid shifts in tissue groups with relatively high perfusion and small volume occur from the intra- to the extracellular spaces. However, the fluid shift in tissue groups with a low perfusion and large volume takes place in the opposite direction. The UF volume and rates, and the size of the sodium (Na+) gradient between the dialysate and blood side of the dialyzer membrane are the most important factors influencing the fluid shifts. Higher UF volumes and flow rates cause an increasing decline in the plasma volume in both SHD and IU. High dialysate sodium concentration (150 mEq L(-1)) helps plasma refilling slightly when compared with a normal dialysate sodium concentration (140 mEq L(-1)). However, a high dialysate sodium concentration is associated with a high plasma sodium rebound, which in turn may lead to interdialytic water intake resulting from thirst and may cause increased weight gain and hypertension.

Lisinopril versus enalapril: evaluation of trough:peak ratio by ambulatory blood pressure monitoring.

In 34 out-patients with essential hypertension, the antihypertensive effect and the trough-to-peak ratios of once-daily enalapril or lisinopril were compared by ambulatory blood pressure monitoring (ABPM) according to a crossover design. The drug dose was titrated and a thiazide diuretic was added if necessary to attain a target office BP of less than 140/90 mm Hg. Both drugs significantly lowered BP but the effect of lisinopril was greater (P < 0.009): day- and night-time mean BP fell from 152/98 and 135/84 mm Hg, respectively to 133/85 and 118/74 mm Hg with enalapril and to 129/83 and 116/70 mm Hg with lisinopril. BP goal was reached with an average dose of 18 mg enalapril with 8 mg hydrochlorothiazide and with 17 mg lisinopril combined with 6 mg diuretic. Trough:peak ratio values, which were calculated after Fourier analysis of ABPM data in individual patients, were independent of drug dose. The combination with the diuretic resulted in slightly higher trough:peak ratios than with ACE inhibitor monotherapy, but the difference was not significant. The median trough:peak ratio in patients when using enalapril-based therapy was 0.48 and, when taking lisinopril-based treatment, it was 0.65 (n = 28, P < 0.005). A significant correlation was found between trough:peak ratio and changes in daytime mean arterial pressure (MAP; Spearman r= 0.43) and night-time MAP (r= 0.66). When 24-h ABPM was performed starting 24 h after last drug intake, both ACE inhibitors still had a significant antihypertensive effect (P < 0.001), which was similar for both drugs. Eleven patients reported minor side effects. Four patients stopped ACE-inhibitor treatment because of cough. The data show that lisinopril has a longer duration of action than enalapril.

Continuous arterio-venous haemodiafiltration: hydraulic and diffusive permeability index of an AN-69 capillary haemofilter.

The dependence of uraemic solute clearance on the hydraulic and diffusive permeability index of an AN-69 capillary haemofilter is investigated during the treatment of patients with continuous arterio-venous haemodiafiltration (CAVHD). A mathematical model is presented to calculate solute clearance and the hydraulic and diffusive permeability index parameters from clinical data and to predict the blood flow rate entering the extra-corporeal circuit from the manufacturer's specifications and blood viscosity. By measuring the flow rates, the patient's mean arterio-venous pressure difference and uraemic solute clearance under different clinical and operational conditions, mathematical model equations are evaluated. During the average survival time of an AN-69 capillary haemofilter of about five days, it is found that both the hydraulic permeability index and the diffusive permeability index decline over treatment time, independent of the haemofilter resistance to blood flow. The measured haemofilter resistance to blood flow is three times higher than the haemofilter resistance predicted from the manufacturer's specifications and blood viscosity. Predicting the blood flow rate entering the extra-corporeal circuit from the arterial haematocrit, plasma protein concentration and temperature and the manufacturer's specifications is not reliable.

Meropenem versus cefuroxime plus gentamicin for treatment of serious infections in elderly patients.

In this multicenter study, the efficacy of and tolerability for meropenem were compared with those for the combination of cefuroxime-gentamicin (+/- metronidazole) for the treatment of serious bacterial infections in patients > or = 65 years of age. A total of 79 patients were randomized; thirty-nine received meropenem (1 g/8 h), and 40 received cefuroxime (1.5 g/8 h) plus gentamicin (4 mg/kg of body weight daily) for 5 to 10 days. Metronidazole (500 mg/6 h) could be added to the cefuroxime-gentamicin regimen for the treatment of intra-abdominal infections (n = 10). Seventy patients were evaluable for clinical efficacy; the primary diagnoses were as follows: pneumonia in 41 patients (20 treated with meropenem, 21 treated with cefuroxime-gentamicin), intra-abdominal infection in 10 patients (7 meropenem, 3 cefuroxime-gentamicin-metronidazole), urinary tract infection (UTI) in 11 patients (6 meropenem, 5 cefuroxime-gentamicin), sepsis syndrome in 7 patients (4 meropenem, 3 cefuroxime-gentamicin), and "other" in 1 patient (cefuroxime-gentamicin). The pathogens isolated from 18 patients with bacteremia were as follows: Staphylococcus spp. (n = 2), Streptococcus spp. (n = 2), members of the family Enterobacteriaceae (n = 11), and Bacteroides spp. (n = 3). A satisfactory clinical response at the end of therapy was achieved in 26 of 37 (70%) and 24 of 33 (73%) evaluable patients treated with meropenem and combination therapy, respectively. Clinical success was achieved in 23 of 31 (74%) and 21 of 28 (75%) evaluable patients with infections other than UTIs, respectively. A satisfactory microbiological response occurred in 15 of 22 (68%) patients in the meropenem group compared with 12 of 19 (63%) treated with combination therapy. Renal failure occurred during therapy in 2 of 39 (5%) meropenem recipients compared with 5 of 40 (13%) of those treated with combination therapy. The findings in this small study indicate that meropenem is as efficacious for and as well tolerated by elderly patients as the combination of cefuroxime-gentamicin (+/- metronidazole).

The use of Fourier analysis in the calculation of trough to peak ratio from ambulatory blood pressure measurements.

The trough:peak (T:P) ratio serves as an index of efficacy of antihypertensive drugs with respect to their dose and dose interval. There is no consensus regarding the method for the calculation of the T:P ratio. We assessed the influences of curve smoothing, the average fall in 24-h mean arterial pressure (MAP) and the length of the peak effect period on the result of T:P ratio calculation. Forty-two patients with essential hypertension (aged 27-81 years; 20 males) had a 24-h ambulatory blood pressure (BP) measurement on two occasions. The first was performed at baseline, the second after 12 weeks of treatment with a beta-blocker, angiotensin-converting enzyme inhibitor, calcium slow-channel blocker, diuretic or a centrally acting drug, all taken once daily. BP data were analysed both by Fourier analysis (FA) with four harmonics and by time block analysis (TBA). The peak effect was defined as the maximum drop in MAP over a period of 0 to 3 h following drug intake at any time in the 24 h, and the trough effect as the fall in MAP over the last 2 h of the dose interval. FA gave higher T:P ratio values than TBA (0.51 vs 0.43; P < 0.05) and the variability of the results was reduced by FA (FA: 0.49-0.52; TBA: 0.35-0.46). A greater fall in 24-h MAP was associated with a higher T:P ratio (r = 0.42, P < 0.02; TBA: r = 0.31, P = 0.09). Half of the patients whose fall in 24-h MAP after treatment was <10 mm Hg, had higher trough BP values, resulting in negative T:P ratios. With increasing length of the peak period, the calculated peak effect was reduced and the T:P ratio increased (both FA and TBA: P < 0.001). The mean trough responses during the last 2 h of the dose interval were similar after TBA and FA. Based on these data, we recommend the use of FA for calculation of T:P ratios, especially when the magnitude of the antihypertensive effect is small. We also suggest using peak- and trough-effect periods of 2 h each. Whenever T:P ratios are calculated, the method used for curve smoothing and the length of peak- and trough-effect periods should be specified in order to obtain meaningful results. T:P ratios need to be interpreted individually together with the magnitude of the antihypertensive drug effect and the circadian BP profile.

An analytical solution to solute transport in continuous arterio-venous hemodiafiltration (CAVHD).

In conventional intermittent hemodialysis, the overall mass transfer coefficient (Kd) of a dialyser is mostly calculated at zero ultrafiltration and at relatively high dialysate flow rates. In continuous arterio-venous hemodiafiltration (CAVHD), the dialysate flow rates are low as comparable to the rates of ultrafiltration flows, making the dialysis treatment as slow as possible. Therefore the overall mass transfer coefficient (Kd) of a CAVHD hemofilter has to be calculated in the presence of ultrafiltration. A mathematical model of CAVHD is presented in order to calculate the diffusive mass transfer coefficient (Kd) for a solute when blood, filtrate and dialysate flow rates and solute concentrations are known. The ultrafiltration volume flux (Jv) is assumed to vary linearly along the axial direction of the hemofilter. The calculated mass transfer coefficient Kd shows that at high values of dialysate flow and low values of ultrafiltration, the overall mass transfer coefficient (Kd) of a CAVHD hemofilter equals mass transfer coefficient (Kd) of a dialyser in conventional intermittent hemodialysis. Also, the calculated mass transfer coefficient Kd shows no significant differences when the ultrafiltration volume flux is assumed to be constant along the length of the hemofilter if no backfiltration occurs in the hemofilter.

High-risk surgical acute renal failure treated by continuous arteriovenous hemodiafiltration: metabolic control and outcome in sixty patients.

The outcome and metabolic control was studied in 60 critically ill patients with acute renal failure (ARF) treated by continuous arteriovenous hemodiafiltration (CAVHD) in a single surgical intensive care unit. Mean age (+/- SEM) was 60 +/- 2 years with a male predominance (80%). The majority of patients required mechanical ventilation (83%) and/or vasopressor support (70%) and suffered from multiorgan failure [mean number of organ system failures 3.3 +/- 0.3 (range 1-6)]. CAVHD resulted in a rapid decline of serum urea and creatinine levels during the first 72 h (urea 47.4 +/- 2.3 to 30.3 +/- 1.4 mmol/l, p < 0.05, and creatinine 572 +/- 27 to 361 +/- 23 mumol/l, p < 0.05); thereafter, controlled steady-state levels were achieved with serum urea levels kept below 30 mmol/l with full protein alimentation and often despite hypotension, surgery and septicemia. Significant electrolyte derangements could be easily corrected and maintained within normal limits. Bicarbonate homeostasis could be restored within 48 h in patients with severe metabolic acidosis (HCO3- < 20 mmol/l) with use of bicarbonate as a buffering anion (17 +/- 0.5 to 23.2 +/- 0.6, p < 0.05). CAVHD allowed rapid removal of excess body and lung water (up to 5 liters/day) without hemodynamic instability. Despite a mean pretreatment APACHE II score of 26.5, 26 patients (43%) survived until discharge from the intensive care unit, of whom 23 (38%) survived to leave hospital. Requirement of mechanical ventilation or vasopressor support, higher APACHE II scores and septicemia were all associated with a poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute dialytic support for the critically ill: intermittent hemodialysis versus continuous arteriovenous hemodiafiltration.

There is still debate about whether continuous renal replacement therapy is superior to intermittent hemodialysis (IHD) as dialytic support for the critically ill patient with acute renal failure, mainly because of lack of comparative data. We sought to address this issue by reviewing the medical records of such patients admitted to a single surgical intensive care unit treated with either continuous arteriovenous hemodiafiltration (CAVHD) or IHD between January 1, 1986, and August 31, 1993. Of 94 consecutive patients who received dialytic support for severe acute renal failure, 34 (36%) patients were treated with IHD and 60 (64%) patients with CAVHD. The patients were comparable in terms of age or gender and represented a similar case mix. Patients treated with CAVHD were more severely ill as manifested by a lower mean arterial pressure (75 +/- 3 vs. 86 +/- 5 mm Hg; p < 0.05), higher Apache II score (26.5 +/- 0.5 vs. 22.2 +/- 0.3; p < 0.05), and a higher number of organ system failures (3.4 +/ 0.2 vs. 2.6 +/- 0.3; p < 0.05). Despite greater illness severity and a higher probability of death (55 +/- 2.6 vs. 33 +/- 2.5%; p < 0.0001), in those treated with CAVHD, no difference in outcome was observed between groups: CAVHD 26/60 (43%) vs. IHD 20/34 (59%; NS). The mean Apache II score of patients treated with CAVHD who survived was similar to that of patients treated with IHD who died (24.5 +/- 0.3 vs. 24.2 +/- 0.4; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Drug clearance by continuous haemodiafiltration. Analysis of sieving coefficients and mass transfer coefficients of diffusion.

In patients who were treated with continuous arteriovenous haemodiafiltration (CAVHD), using the AN-69 capillary dialyser, we measured the clearance rates of uraemic solutes and drugs at dialysate flow rates of 0, 1 and 3 l/h. By using a mathematical model of CAVHD, we analysed the data in terms of sieving coefficients and diffusive mass transfer coefficients. These parameters proved to be related to drug protein binding and molecular weight. The parameter values may be used to calculate the expected drug clearance rate under different operating conditions.

Clearance of imipenem/cilastatin in acute renal failure patients treated by continuous hemodiafiltration (CAVHD).

In patients with acute renal failure, who were treated with continuous arteriovenous hemofiltration (CAVH) or continuous arteriovenous hemodiafiltration (CAVHD), we measured clearance rates of imipenem and cilastatin (Tiënam-500). Literature data on volume of distribution and on the endogenous clearance in normals and in anuric patients and the observed clearance rates by CAVH/CAVHD were used to develop guidelines for dose adaptations. Based on the desired peak levels of imipenem, normal subjects should receive the fixed imipenem/cilastatin dose combination (500 mg/500 mg) q.i.d. and patients with acute renal failure should receive the same dose b.i.d. After starting treatment with either CAVH, CAVHD or continuous venovenous hemofiltration (CVVH), no further dose adjustment is necessary. The non-renal clearance rate of cilastatin is very low compared to that of imipenem. If a patient develops anuria, the clearance rate of imipenem decreases from the normal value of 245 ml/min to 116 ml/min. Clearance rate of cilastatin, however, decreases from 230 ml/min to 3 ml/min. Therefore, in patients with renal failure accumulation of cilastatin will occur. On the other hand, if the patient is treated by CAVHD, the relative contribution of the dialyser clearance to the total drug clearance is much greater for cilastatin than for imipenem. As a result, the accumulation of cilastatin is reversed. During treatment by CAVHD, the clearance rate of imipenem raises 15%-25% and that of cilastatin 335%-600%. For this reason, we conclude that the use of the fixed dose combination (500 mg/500 mg) b.i.d. in patients with acute renal failure treated by CAVHD may be justified.

Blood flow, ultrafiltration and solute transport rate in continuous arteriovenous haemodiafiltration: the AN-69 flat-plate haemofilter.

We measured blood flow, ultrafiltration rate and uraemic solute clearance at different dialysate flow rates during CAVHD using the AN-69 0.43 m2 flat plate haemofilter. As filter performance depends on clinical conditions and operational characteristics, data were analysed in terms of resistance to blood flow, membrane index of ultrafiltration, and diffusive mass transfer coefficients. An attempt was made to construct nomograms that may be used both to predict filter performance and to compare different haemofilters with each other.