Netilmycin and vancomycin in the treatment of peritonitis in CAPD patients.

This study was undertaken to evaluate: 1. The efficacy of netilmycin and vancomycin as combined first line antimicrobial regime, compared to cefuroxime, in the treatment of peritonitis. 2. To measure the levels of netilmycin and vancomycin in the serum and dialysate. 3. To report on the use of this combination over a one year period and compare it with that of cefuroxime used during the previous one year.

The use of glucose polymer (icodextrin) in peritoneal dialysis: an overview.

The osmotic effectiveness of glucose polymer is now well established. The relative inertness of this macromolecular compound has been the key factor in its success as the first "colloid" osmotic agent in clinical use. In its present form it sustains ultrafiltration for up to 12 hours, and a daily overnight use would obviate the need for hypertonic exchanges, especially 3.86% glucose. In addition, it could be used in automated peritoneal dialysis regimens to enhance ultrafiltration and solute clearance during the daytime. Preliminary reports also indicate that it is beneficial in diabetic patients and in some patients who have lost ultrafiltration. Although systemic accumulation of glucose polymer breakdown products occurs, it reaches steady-state levels quickly (within 2 weeks) and remains stable throughout the duration of polymer use. In the long-term study these levels of maltose and oligosaccharides over 2.5 years represent the longest exposure of these substances in uremic patients without any clinical or metabolic adverse effects and provides important evidence of its safety. Future work based on ongoing studies suggests that a family of physiological solutions ("bimodal" preparations in iso-osmolar combination) could be available, and the individual's dialysis prescription could be tailored to take into account the ultrafiltration and metabolic needs. Icodextrin will be a key component of such solutions.

Optimal use of glucose polymer (icodextrin) in peritoneal dialysis.

The osmotic effectiveness of glucose polymer is now well established. The relative inertness of this macromolecular compound has been the key factor in its success as the first "colloid" osmotic agent in clinical use. In its present form, it produces sustained ultrafiltration for up to 12 hours, and a daily overnight use would obviate the need for hypertonic exchanges, especially 3.86% glucose. In addition, it could be used in automated peritoneal dialysis regimes to enhance ultrafiltration and solute clearance during the daytime. Preliminary reports also indicate that it is beneficial in diabetic patients and in some patients who have lost ultrafiltration. The new "bimodal" formulations look promising, with the potential to replace all the currently used hyperosmolar exchanges with physiological solutions. Although systemic accumulation of glucose polymer breakdown products occurs, it reaches steady-state levels quickly (within two weeks) and remains stable throughout the duration of polymer use. In the long-term study, these levels of maltose and oligosaccharides over three-and-a-half years represent the longest exposure of these substances in uremic patients without any clinical or metabolic adverse effects and provide an important evidence of safety. Future work based on studies that are ongoing suggest that a family of physiological solutions ("bimodal" preparations in iso-osmolar combination) could be available, and the individual's dialysis prescription could be tailored to take into account the ultrafiltration, metabolic needs, as well as the long-term viability of the membrane. Glucose polymer will be a key component of such solutions.

Peritonitis occurrence in a multicenter study of icodextrin and glucose in CAPD. MIDAS Study Group. Multicenter Investigation of Icodextrin in Ambulatory Dialysis.

OBJECTIVE: To compare peritonitis occurrence and outcome in a large U.K. study Multicentre Investigation of Icodextrin in Ambulatory Dialysis (MIDAS). DESIGN: Prospective, randomized, controlled 6-month comparison of icodextrin with glucose for the long dwell in continuous ambulatory peritoneal dialysis (CAPD) patients. SETTING: Eleven CAPD units in U.K. teaching hospital. PATIENTS: A total of 209 patients established on CAPD for at least 3 months (103 control, 106 icodextrin). Twenty-three control (C) and 22 icodextrin (I) patients experienced peritonitis during the study. INTERVENTION: Patients who had peritonitis remained on treatment (unless CAPD was withdrawn, temporarily or permanently). MAIN OUTCOME MEASURES: The main outcome measures were the rate of peritonitis and duration of CAPD treatment prestudy; the rate of peritonitis episodes and their outcome during study; the effect of peritonitis on laboratory variables, serum icodextrin metabolites, and ultrafiltration efficacy. RESULTS: Prestudy: Nine (39%) of C but 14 (64%) of I patients had suffered previous peritonitis episode(s), with overall rates of 0.58 and 0.78 episodes per patient-year, respectively. DURING STUDY: There were 31 C episodes and 35 I episodes, with overall rates of 0.76 and 0.93 per patient-year, respectively. The increase in the C and I groups was 31% and 19%, respectively. Serum osmolality and sodium levels were unaffected by peritonitis, and there was no increase in serum icodextrin metabolites during peritonitis. Overnight ultrafiltration volume during peritonitis (mean +/- SD) declined slightly from 218 +/- 354 mL to 185 +/- 299 mL (NS) in the control group, but increased in the icodextrin group from 570 +/- 146 mL to 723 +/- 218 mL (p < 0.01). CONCLUSIONS: Using icodextrin for the long dwell in CAPD does not increase the rate of peritonitis, nor does it alter the outcome of peritonitis. Peritonitis does not affect uptake of icodextrin from the peritoneum.

Cell function and viability in glucose polymer peritoneal dialysis fluids.

OBJECTIVE: To investigate the biocompatibility profile of a new peritoneal dialysis fluid containing glucose polymer (GPF). DESIGN: Viability and function of peripheral neutrophils (PMN) from healthy donors and cultured human peritoneal mesothelial cells were assessed in vitro after exposure to dialysis fluids. Phagocytosis, leukotriene B4 synthesis, and respiratory burst activation were measured following stimulation with serum-treated zymosan (STZ) or opsonized Staphylococcus epidermidis (S. epidermidis). Bacterial growth in the fluids was also investigated. In vivo pH equilibration of GPF and subsequent respiratory burst activation following incubation in spent dialysate were studied. RESULTS: For all the host defense parameters measured, commercial dialysis fluids (Dianeal; 1.36% and 3.86% glucose) and GPF (pH 5.2) were significantly more inhibitory than the control buffer (pH 7.3). Mesothelial cell viability was reduced by all the fluids tested irrespective of pH. Glucose polymer fluid was significantly more inhibitory than Dianeal 1.36% for STZ phagocytosis and respiratory burst activation. In contrast, it was less suppressive than Dianeal 3.86% for LTB4 synthesis. For all parameters tested, except LTB4 generation, there was a marked effect of pH, with GPF being significantly more inhibitory at pH 5.2 than at pH 7.3. None of the fluids tested supported the growth of S. epidermidis, although the viable counts in GFP were significantly higher than in Dianeal. Fluid inhibition of PMN respiratory burst activation and cytotoxicity were reduced in a time-dependent manner following increasing dwell time in vivo. CONCLUSIONS: GPF does not appear to be significantly different from Dianeal as far as host defense parameters are concerned. However, the cell viability and bacterial survival data suggest some possibly negative aspects of this fluid formation.

Recovery from sensorineural deafness in Wegener's granulomatosis.

Wegener's granulomatosis may present with deafness or other aural symptoms. This report describes two patients with histological evidence of Wegener's granulomatosis who developed reversible sensorineural hearing loss during the course of their illness. The first patient showed complete recovery of a sensorineural hearing loss averaging 50 dB after ten months treatment with cyclophosphamide and high-dose prednisolone. The second patient, who was on maintenance haemodialysis, achieved a 40 dB improvement in sensorineural hearing loss within two weeks of adding cyclophosphamide to pre-existing corticosteroid therapy. These findings suggest that the prognosis of sensorineural hearing loss in Wegener's granulomatosis can be improved with suppression of the vasculitic process by early treatment with combined cytotoxic-immunosuppressive therapy.

Incidence of advanced chronic renal failure and the need for end stage renal replacement treatment.

OBJECTIVE: To determine the age related incidence of advanced chronic renal failure in two areas of England. DESIGN: Prospective study of patients newly identified as having advanced chronic renal failure within a two year period; subsequent monitoring of patients' clinical course for a further 26 months. SETTING: Devon and Blackburn. SUBJECTS: Those patients in a population of 708,997 who developed advanced chronic renal failure (serum creatinine concentration greater than 500 mumol/l) for the first time during a two year period. MAIN OUTCOME MEASURES AND RESULTS: 210 Patients (148 per million population per year) developed advanced chronic renal failure, 117 (51%) of whom were over 70. The age related incidence rose from 58 per million per year in those aged 20-49 to 588 per million per year in those aged 80 or over. Only 54% (113) of patients were referred to a nephrologist; 120 patients (57%) needed dialysis or died within three months of presenting without receiving dialysis, and 187 (89%) died or needed dialysis within three years. After those unsuitable for further treatment had been excluded, 78 patients per million population per year aged under 80 needed to start long term renal replacement treatment. CONCLUSIONS: Many patients suitable for renal replacement treatment are still not referred for nephrological opinion and are denied treatment. If the treatment rate in the United Kingdom rose from the 1988 rate of 55.1 per million per year to 78 per million per year then the number of patients receiving treatment would rise to about 800 per million. This is double the present number and has considerable but predictable resource implications for the NHS.

Alternative osmotic agents.

After a decade of experience with continuous ambulatory peritoneal dialysis, several long-term complications are emerging which relate either directly (ultrafiltration of short duration, metabolic derangements) or indirectly (hyperosmolality, low pH) to the use of glucose as an osmotic agent. These considerations have motivated the search for an alternative to glucose. Some of the substances which have been proposed to replace it have been reviewed.

Can ultrafiltration occur with a hypo-osmolar solution in peritoneal dialysis?: The role for 'colloid' osmosis.

1. In peritoneal dialysis the removal of excess body water (ultrafiltration) is traditionally achieved by means of dialysis solution made hypertonic to plasma by the addition of an osmotic agent. In vitro, the osmotic flow may be directed against the osmolality gradient by using a hypo-osmolar solution, but this phenomenon has not previously been applied to clinical peritoneal dialysis. 2. The ultrafiltration performances of hypo-osmolar dialysis solutions containing a high-molecular-weight glucose polymer (weight average molecular weight 22,000), isolated by fractionation of hydrolysed corn starch, were compared with those of hypertonic glucose solutions over a 12 h exchange in 11 patients well established on continuous ambulatory peritoneal dialysis. 3. Five per cent (272 +/- 1.1 mosmol/kg) and 7.5% (277 +/- 2.0 mosmol/kg) glucose polymer solutions produced net ultrafiltration of 243 +/- 53 and 526 +/- 59 ml that were significantly greater than the ultrafiltration of -48 +/- 96 and 223 +/- 84 ml associated with 1.36% (339 +/- 1.9 mosmol/kg) and 2.27% (393 +/- 3.2 mosmol/kg) glucose solutions, respectively. The net ultrafiltration with 10% glucose polymer (284 +/- 2.0 mosmol/kg) and 3.86% glucose (482 +/- 1.6 mosmol/kg) solutions were similar (699 +/- 48 versus 708 +/- 82 ml). 4. The transperitoneal absorption of glucose polymer was substantially lower than that of glucose solutions as was the potential calorie load per millilitre of ultrafiltrate. 5. The addition of 0.35% glucose (molecular weight 180) to 7.5% glucose polymer solution raised the dialysate osmolality to an iso-osmolar level (299 +/- 0.8 mosmol/kg) and produced ultrafiltration which was 29% greater than with 7.5% glucose polymer solution alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Single daily overnight (12-h dwell) use of 7.5% glucose polymer (Mw 18700; Mn 7300) +0.35% glucose solution: a 3-month study.

The osmotic effectiveness of an isosmolar glucose polymer (GP) solution during long-dwell (8-12 h) peritoneal dialysis has been demonstrated. The absorption of GP, though only a fraction of currently used glucose, is usually accompanied by the systemic accumulation of its breakdown product, maltose. The long-term consequences of maltose accumulation remain unknown. We studied the accumulation pattern of GP fractions, changes in serum electrolytes, osmolality, and adverse reaction profile over a 3-month period using a daily regime of an overnight exchange of 7.5% GP+0.35% glucose solution with three daytime exchanges of 1.36% glucose in five non-diabetic CAPD patients. The GP solution (299 +/- 0.7 mOsm/kg) produced mean daily overnight UF of 589 ml and maintained stable serum biochemistry. The mean serum maltose level increased from a predialysis value of 0.03 +/- 0.08 g/l to a steady-state level of 1.1 +/- 0.14 g/l within 2 weeks and remained stable throughout the study. This did not influence serum osmolality or sodium and produced no significant adverse effects. Once-daily overnight use of an isosmolar GP solution is safe and effective. The accumulation of maltose reaches steady-state levels quickly and produces no adverse toxic effects in the short term. Further long-term studies are planned.

A randomized multicenter clinical trial comparing isosmolar icodextrin with hyperosmolar glucose solutions in CAPD. MIDAS Study Group. Multicenter Investigation of Icodextrin in Ambulatory Peritoneal Dialysis.

The osmotic effectiveness of a large molecular weight glucose polymer fraction (Icodextrin) as a novel "colloid" osmotic agent in peritoneal dialysis was established, but the long-term safety remained undetermined. A randomized, controlled multicenter investigation of Icodextrin in ambulatory peritoneal dialysis (MIDAS) was undertaken to evaluate the long-term safety and efficacy by comparing daily overnight (8 to 12 hr dwell) use of isosmolar Icodextrin (282 mOsm/kg) with conventional 1.36% (346 mOsm/kg) and 3.86% (484 mOsm/kg) glucose exchanges over six months. Two hundred and nine patients were randomized from 11 centers, with 106 allocated to receive Icodextrin (D) and 103 to remain on glucose (control group; C); 138 patients completed the six month study (71 C, 67 D). All patients were divided into weak (1.36%) or strong (3.86%) subgroups based on their use of glucose solutions overnight during the pretreatment baseline period. The mean (+/- SEM) overnight ultrafiltration (UF) with D was 3.5 times greater than 1.36% glucose at eight hours [527 +/- 36 vs. 150 +/- 47 ml; 95% confidence interval (CI) for the difference +257 to +497 ml; P < 0.0001] and 5.5 times greater at 12 hours (561 +/- 44 vs. 101 +/- 48 ml, 95% CI for the difference +329 to +590; P < 0.0001) and no different from that of 3.86% glucose at eight hours (510 +/- 48 vs. 448 +/- 60 ml, 95% CI for the difference -102 to +226 ml; P = 0.44) and at 12 hours (552 +/- 44 vs. 414 +/- 78 ml, 95% CI for the difference -47 to +325 ml; P = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrafiltration with an isosmotic solution during long peritoneal dialysis exchanges.

The potential of a starch-derived glucose polymer (molecular weight 16,800) as an osmotic agent for peritoneal dialysis was evaluated. A dialysate isosmotic to uraemic serum (302 [SEM 1.3] mOsm/kg) containing 5% glucose polymer (9.4 mmol/l) was compared with hypertonic (332 [1.0] mOsm/kg) 1.36% glucose (76 mmol/l) solution for ultrafiltration, solute transport, and carbohydrate absorption over 6 h and 12 h peritoneal dialysis exchanges. Glucose polymer solution produced substantially greater net ultrafiltration than glucose, while maintaining stable dialysate osmolality throughout the exchanges. At 6 h and 12 h, 14.4% and 28.1% of glucose polymer had been absorbed, compared with 61.5% and 83.0% of glucose; thus, glucose polymer provided less than 50% of the calorie load of the glucose dialysate per unit volume of ultrafiltrate. There was a 7-9-fold increase in serum maltose with glucose polymer. This high-molecular-weight glucose polymer produced sustained ultrafiltration even when dialysate osmolality remained within the physiological range, by a mechanism resembling "colloid" osmosis. It is a safe and effective osmotic agent but its long-term effects need further study.

Effects of sulindac on renal function and prostaglandin synthesis in patients with moderate chronic renal insufficiency.

The renal effects of therapeutic doses of sulindac were studied in nine patients with stable renal insufficiency, mean creatinine clearance 37.0 +/- 2.2 ml min-1 1.73 m-2 (range 24.7-54.6 ml min-1 1.73 m-2). Nine days' treatment with sulindac produced a small, but significant, reduction in the mean creatinine clearance (37.0 +/- 2.2 to 34.7 +/- 2.2 ml min-1 1.73 m-2; P less than 0.02) and 99mTc diethylenetriaminepenta-acetate (DTPA) clearance (35.5 +/- 3.4 to 31.4 +/- 3.6 ml min-1 1.73 m-2; P less than 0.02) without altering body weight, effective renal plasma flow [131I]hippuran clearance), plasma renin activity (PRA), 24 h urinary volume or electrolyte excretion. After discontinuation of sulindac, creatinine clearance returned to pretreatment values. In five female patients, pretreatment urinary excretion of the 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a stable breakdown product of prostacyclin (PGI2), was significantly reduced (P less than 0.02) when compared with four healthy controls, whereas prostaglandin E2 (PGE2) was unchanged. Administration of sulindac did not significantly alter the excretion rate of PGE2 or 6-ketoPGF1 alpha in this group of patients. In chronic renal disease with moderate renal impairment, reduced renal prostacyclin synthesis may be an important predisposing factor to the renal toxicity associated with the use of non-steroidal anti-inflammatory drugs (NSAID). Short term use of sulindac in therapeutic doses does not appear to influence the excretion of prostaglandins and produces only a minor reversible change in renal function; used cautiously it may have advantages over other NSAID in these patients.

Kinetic and clinical studies of beta 2-microglobulin in continuous ambulatory peritoneal dialysis: influence of renal and enhanced peritoneal clearances using glucose polymer.

A risk of beta 2-microglobulin (beta 2-M)-associated amyloidosis in long-term CAPD patients has been recognised. We examined the kinetics of beta 2-M and potential clinical manifestations of amyloidosis in patients well-established on CAPD for 1-76 months (mean +/- SEM; 16.4 +/- 14 months). In 57 patients, serum beta 2-M concentration was elevated to 30 +/- 1.8 (mean +/- SEM, mg/l) and correlated positively with the duration on CAPD. In 18 patients studied with variable degrees of residual renal function, serum beta 2-M concentration increased with declining renal function; this was most marked when the creatinine clearance was less than 1 ml/min. Using an isosmolar solution (302 +/- 1.3 mOsm/kg) containing 5% glucose polymer (9.4 mmol/l; MW 16,800), the transperitoneal elimination of beta 2-M was significantly enhanced (1.6 times) compared to conventional 1.36% glucose solution, but without a detectable change in serum concentrations during a 6-h study. No significant difference was found between the estimated minimum volume of distribution of beta 2-M in CAPD and haemodialysis patients. Symptomatic amyloid-associated disease was absent in patients in this study, and may be attributed to the short duration of dialysis.