The efficacy of once weekly compared with two or three times weekly subcutaneous epoetin beta: results from a randomized controlled multicentre trial. Swedish Study Group.

BACKGROUND: Anaemia in haemodialysis patients can be effectively treated with erythropoietin. We investigated whether subcutaneous (SC) epoetin ss administered once weekly was as effective as the same weekly dosage given in two to three divided doses. METHODS: One hundred and fifty-eight patients (delivered Kt/V >1.0, where K=dialyser-renal urea clearance, t=dialysis time and V=filtration volume, obtained by urea kinetic modelling) were randomized to treatment with SC epoetin beta either once weekly (n=118), or to their original dosage two or three times weekly (control group, n=40) for 24 weeks. All patients received intravenous iron supplementation when necessary. RESULTS: Eight-eight patients in the once weekly group and 30 patients in the control group were treated for at least 16 weeks and are included in the analysis. Stable haemoglobin levels were maintained without epoetin dose increases in 73% of patients in both groups. Mean haemoglobin levels at randomization and after 16 and 24 weeks were 11.4, 11.1 and 11.1 g/dl, respectively, in the once weekly group compared with 11.2, 11.3 and 11.2 g/dl, respectively, in the control group. The mean weekly epoetin beta dosages at randomization and after 16 and 24 weeks were 102, 103 and 106 IU/kg bodyweight, respectively, in the once weekly group compared with 109, 109 and 115 IU/kg bodyweight, respectively, in the control group. No statistically significant between-group differences were apparent for changes in haemoglobin levels or epoetin beta dosages at week 24. CONCLUSIONS: Once weekly SC administration of epoetin beta is as safe and effective in maintaining haemoglobin levels in stable haemodialysis patients as two or three times weekly administration of the same total dose. By using the once weekly regimen, patients can avoid up to 104 injections per year. This would reduce clinic time for patients who do not self administer, and may also encourage self-administration and improve overall compliance.

Impaired effect by NO synthase inhibition on tubuloglomerular feedback in rats after chronic renal denervation.

Acute unilateral renal denervation (aDNX) is associated with reduced tubuloglomerular feedback (TGF) sensitivity. Six days after denervation (cDNX) TGF sensitivity is somewhat restored, but TGF reactivity increased. This study aimed to investigate if the increased TGF reactivity that was seen in cDNX kidneys was owing to reduced production of nitric oxide (NO). TGF characteristics were determined with micropuncture experiments in anaesthetized rats, using the stop-flow pressure (PSF) technique. Maximal drop in PSF (DeltaPSF) was used as an index of TGF reactivity and the loop of Henle perfusion rate that elicited half-maximal DeltaPSF, the turning point (TP) was used as a measure of TGF sensitivity. In cDNX kidneys, TP was higher than in control rats (25.4 +/- 1.5 nL min-1 vs. 19.1 +/- 1.1 nL min-1), but clearly lower than in aDNX rats (37. 3 +/- 3.1 nL min-1). TGF was more reactive in cDNX rats (DeltaPSF=14. 7 +/- 1.1 mmHg) than in aDNX (7.9 +/- 1.1 mmHg) and control rats (9. 6 +/- 0.9 mmHg). Intratubular inhibition of NO synthase N omega-nitro-L-arginine (L-NA) in sham-DNX animals, decreased TP to 13.9 +/- 2.2 nL min-1 and DeltaPSF was increased with 92%. In cDNX kidneys TP was not significantly reduced by L-NA, and TGF reactivity was only moderately increased by 31%. Intratubular infusion of L-arginine (L-Arg) reduced DeltaPSF from 10.2 +/- 0.7 to 6.5 +/- 0.6 mmHg in sham-DNX kidneys, but TP was unaffected. In cDNX kidneys, there was no effect on either DeltaPSF or TP by the addition of L-Arg. However, when NO was delivered via sodium nitroprusside in the tubular perfusate, a clear reduction of DeltaPSF was seen in both sham-DNX and cDNX kidneys (from 9.9 +/- 0.5 to 4.4 +/- 1.0 and from14.9 +/- 1.3 to 8.1 +/- 1.5 mmHg, respectively). This indicates that cDNX is a state of low renal NO production and that this low level of NO resets TGF to a higher sensitivity and more pronounced reactivity.

Does post-angiographic hemodialysis reduce the risk of contrast-medium nephropathy?

OBJECTIVE: Several strategies have been employed to reduce the incidence of nephrotoxicity in connection with the administration of urographic contrast media. We present the results of a randomized study to explore the effect of a single hemodialysis treatment immediately after an angiographic examination. MATERIAL AND METHODS: The patients studied had moderately reduced renal function. Seventeen of the 32 patients had diabetic nephropathy and 15 had other renal diseases. They were randomly selected to undergo either hemodialysis or standard treatment following the angiographic examination. The glomerular filtration rate (GFR) was determined the day before and 1 week after administration of the contrast medium. All patients were hydrated and received oral calcium-channel blocking treatment before angiography. RESULTS: Hemodialysis lowered the level of contrast medium in plasma by approximately 80%. In spite of this no significant difference in renal iohexol clearance was noted between groups treated and not treated with hemodialysis. CONCLUSIONS: The risk of a marked and sustained reduction in renal function after administration of an iodine contrast medium is low with modern angiographic techniques. Hemodialysis reduces levels of contrast media in plasma but does not reduce the incidence of contrast-medium-induced nephrotoxicity in the GFR range from 10 to 25 ml/min.

Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis. A Swedish multi-center study.

A therapeutic removal of antibodies may be achieved by immunoadsorption (IA) or by plasma exchange (PE). The aim of this prospective randomised study was to compare the efficacy of these different techniques with regard to treatment of patients with rapidly progressive glomerulonephritis (RPG) having at least 50% crescents. Forty-four patients with a RPG were included for treatment either by IA or PE (with albumin as substitution for removed plasma). All patients were additionally treated with immunosuppression. A median of 6 sessions of PEs were performed in 23 patients compared with 6 IAs in 21 patients. Goodpasture's syndrome (GP) was present in 6 patients (PE 3, IA 3). All of them started and ended in dialysis, two died. Among the remaining 38 patients (26 men, 12 women) 87% had antibodies to ANCA. Creatinine clearance for PE versus IA were at a median at start 17.1 and 19.8 ml/min, and at 6 months 49 and 49 ml/min, respectively. At 6 months 7 of 10 patients did not need dialysis (remaining: IA 0/5 and PE 2/5, n.s.). The extent of improvement did not differ between the groups. Three patients died during the observation period of 6 months (IA 2; PE 1, on HD). Although no difference was found between the IA or the PE group this study shows that the protocol used was associated with an improved renal function in most patients (except for Goodpasture's syndrome) whereas 70% of them could leave the dialysis program.

Renal nerve stimulation restores tubuloglomerular feedback after acute renal denervation.

Renal nerves play an important role in the setting of the sensitivity of the tubuloglomerular feedback (TGF) mechanism. We recently reported a time-dependent resetting of TGF to a lower sensitivity 3-4 h after acute unilateral renal denervation (aDNX). This effect persisted after 1 week, but was then less pronounced. To determine whether normal TGF sensitivity could be restored in aDNX kidneys by low-frequency renal nerve stimulation (RNS), the following experiments were performed. Rats with aDNX were prepared for micropuncture. In one experimental group proximal tubular free flow (Pt) and stop flow pressures (Psf) were measured during RNS at frequencies of 2, 4 and 6 Hz. In another series of experiments the TGF sensitivity was evaluated from the Psf responses at different loop perfusion rates after 20 min of RNS at a frequency of 2 Hz. The maximal drop in Psf (delta Psf) and the tubular flow rate at which half the maximal response in delta Psf was observed (turning point, TP), were recorded. At RNS frequencies of 2, 4 and 6 Hz, Pt decreased from the control level of 14.1 +/- 0.8-13.1 +/- 1.0, 12.4 +/- 1.1 and 11.2 +/- 0.8 mmHg (decrease 21%, P < 0.05), respectively, while at zero perfusion and during RNS at 2 and 4 Hz Psf decreased from 42.5 +/- 1.6 to 38.2 +/- 1.4 and 32.8 +/- 4.3 mmHg (decrease 23%, P < 0.05), respectively. The TGF characteristics were found to be reset from the normal sensitivity with TP of 19.0 +/- 1.1 nL min-1 and delta Psf of 8.7 +/- 0.9 mmHg to TP of 28.3 +/- 2.4 nL min-1 (increase 49%, P < 0.05) and delta Psf of 5.8 +/- 1.2 mmHg (decrease 33%) after aDNX. After 20 min of RNS at 2 Hz TP was normalized and delta Psf was 33% higher. Thus the present findings indicate that the resetting of the TGF sensitivity that occurred 2-3 h after aDNX could be partially restored by 20 min of RNS at a frequency of 2 Hz. These results imply that renal nerves have an important impact on the setting of the sensitivity of the TGF mechanism.

Effects of acute and chronic unilateral renal denervation on the tubuloglomerular feedback mechanism.

We recently observed a time-dependent resetting of the tubuloglomerular feedback (TGF) sensitivity to a subnormal level after acute unilateral renal denervation (aDNX). The present investigation compares the effects of aDNX with those of chronic unilateral renal denervation (cDNX), i.e one week after aDNX. All experiments were performed in anaesthetized rats prepared for micropuncture. cDNX led to increases in urine, sodium and potassium excretion in denervated kidneys, while contralateral kidneys showed reduced excretion of these parameters. GFR was increased in denervated kidneys, but unchanged on the contralateral side. TGF activity was determined by measuring the maximal stop-flow pressure response (delta Psf) and the tubular flow rate at which 50% of the maximal response occurred (turning point; TP). cDNX decreased TGF sensitivity, as indicated by an increased TP from 19.1 nL/min in sham-DNX to 26.1 nL/min. Concomitantly, TP in contralateral kidneys was significantly decreased to 15.9 nL/min, aDNX led to a greater sensitivity reduction: TP increased from 19.8 to 34.0 nL/min and contralaterally TP decreased to 14.0 nL/min. delta Psf in cDNX increased by 63% compared to sham-DNX, while on the contralateral side this was unchanged. No difference in delta Psf was found between control, DNX and contralateral kidneys in the aDNX group. In summary, these experiments show that the previously reported decrease in TGF sensitivity in aDNX kidneys still persists after one week, although less pronounced. As a result of the decreased TGF sensitivity, GFR is kept on a high level in cDNX kidneys. Contralateral kidneys show reversed resetting.

Intensive hemodialysis and hemoperfusion treatment of Amanita mushroom poisoning.

Over a period of fifteen years, 41 patients including 23 males and 18 females with Amanita mushroom poisoning were treated at the University Hospital of Lund, Sweden. The intensity of poisoning was graded according to serum transaminase elevations and prothrombin time reductions. Severity was mild in 16 patients (Group A), moderate in 14 (Group B) and severe in 11 (Group C). Members of Group C reported shorter latency periods before the onset of symptoms, (10 +/- 1 hours, P < 0.05) and longer delays in treatment, (34 +/- 4 hours), than did the other patients. Intensive treatment was begun before the results of urine amatoxin assay were reported. Treatment consisted of: fluid and electrolyte replacement, oral activated charcoal and lactulose, i.v. penicillin, combined hemodialysis and hemoperfusion in two 8 hour sessions, some received i.v. thioctic acid, other i.v. silibinin, all received a special diet. This combination of treatment modalities was used to accelerate the elimination of amatoxin from the patients' bodies. The longest period of hospitalization, 13 +/- 2 days, was required by the patients of Group C (p < 0.01). All patients improved and were discharged from the hospital asymptomatic. No sequelae were later reported for the majority of those moderately and severely poisoned. We have concluded that intensive combined treatment applied in these cases is effective in relieving patients with both moderate and severe amanitin poisoning.

Intensified dialysis treatment of ethylene glycol intoxication.

During a period of 10 years 18 men were treated for severe ethylene glycol (EG) intoxication. All patients received supportive measures and ethanol infusion. Hemodialysis (HD) was applied in 11 patients (Group I) whereas 7 patients, who exhibited more advanced toxicity symptoms, received peritoneal dialysis (PD) simultaneously with HD (Group II). Patients in Group II showed more advanced acidosis on admission than in Group I (Base excess -27.1 mmol/l versus -16.8 mmol/l, p < 0.0075). The results of treatment in these two groups of patients were compared. All patients in Group I survived and one patient in Group II died. The patients in Group II were discharged with higher serum creatinine and follow up time to improve renal function was longer than in Group I (252 versus 149 mumol/l, p < 0.015 and 23 versus 7.9 weeks, p < 0.05 respectively). No correlations were found between serum EG and grade of acidosis on admission or serum EG and subsequent increase of serum creatinine but acidosis on admission was highly correlated to the rise of serum creatinine after the 72 hours of observation time (p < 0.0001). It is concluded, that combined HD and PD treatment was beneficial in the presented patients as it corrected acidosis earlier and could eliminate EG and its toxic metabolites faster, improving prognosis.

Acute renal denervation causes time-dependent resetting of the tubuloglomerular feedback mechanism.

Renal effects of acute renal denervation (DNX) were studied in anaesthetized rats. In a first series, whole kidney clearance measurements were made 120 and 240 min after unilateral DNX. At 240 min, urine production was 3.59 +/- 0.87 microL min-1 in control kidneys and 7.74 +/- 1.97 microL min-1 in denervated kidneys. The corresponding values for sodium excretion were 0.56 +/- 0.17 and 1.41 +/- 0.34 mumol min-1, potassium excretion 0.48 +/- 0.08 and 0.97 +/- 0.37 mumol min-1 and glomerular filtration rate (GFR) 0.83 +/- 0.08 and 1.05 +/- 0.16 mL min-1, respectively. In a second series, tubuloglomerular feedback (TGF) characteristics were determined with the stop-flow pressure (Psf) technique. With increasing time, the sensitivity of the TGF mechanism diminished in denervated rats, as indicated by an increased turning point (TP). TP was significantly increased 2 h after DNX from 19.1 +/- 1.13 in control to 25.9 +/- 1.10 nL min-1. TP was further increased 4 h after DNX to 37.3 +/- 3.12 nL min-1. However, the maximal TGF response to increased flow in the late proximal tubule was not altered. But, Psf was significantly higher in DNX rats than in the controls (47.4 +/- 1.01 vs. 43.0 +/- 1.53 mmHg) in spite of a lower blood pressure (107 +/- 2.9 vs. 119 +/- 2.2 mmHg). We conclude that intact renal nerves are essential for the setting of the TGF sensitivity and hence the regulation of GFR.

Hemodialysis for elimination of the nonionic contrast medium iohexol after angiography in patients with impaired renal function.

We examined the kinetics of contrast agent elimination during hemodialysis in 7 patients with end-stage renal disease on regular hemodialysis treatment (group I) and in 13 patients with impaired renal function (serum creatinine 214-657 mumol/l; group II). The nonionic agent iohexol was administered at a dose of 0.4-4.5 g/kg, and a 6-hour hemodialysis was performed with 1-18 h delay. This procedure removed 60-90% (mean 77%) of the iohexol present in the circulation at the start of dialysis treatment. The mean extraction ratio across the dialysis membrane was 0.47 and was inversely related to blood flow. The total clearance of iohexol was 70.4 +/- 24.6 ml/min and was very close to dialyzer clearance, as estimated from blood flow and extraction ratio. The plasma iohexol level after dialysis was related to the dose administered, iohexol clearance, and the patients' body weight. During peritoneal dialysis (36-60 liters dialysis fluid), 43-72% of the iohexol dose was removed from the patients' circulation. In patients of group II no further impairment of the renal function (increase of serum creatinine) in conjunction with angiography was observed. We conclude that hemodialysis and peritoneal dialysis are effective methods for removal of iohexol. Our observations suggest also that accelerated elimination of contrast media by prophylactic dialysis can be beneficial in preventing further reduction in renal function after angiographic procedures in high-risk patients.

Genotyping of hepatitis C virus isolates by a modified polymerase chain reaction assay using type specific primers: epidemiological applications.

A polymerase chain reaction (PCR)-based assay using primers against the hepatitis C core gene has been described [Okamoto et al. (1992a): Journal of General Virology 73:673-679]. Within the two major HCV genotypes 1 and 2, the Okamoto system identifies two subtypes each (1a, 1b and 2a, 2b, respectively). Typing is achieved by a primary PCR with consensus primers followed by a nested PCR with type specific primers. The original assay was modified by addition of a parallel second PCR identifying the recently described major genotype 3. The assay also identifies in duplicate subtype 1b (type II by Okamoto), suggested to respond poorly to interferon. Reaction conditions were reviewed and melting temperatures of all typing primers equalised to increase strigency. The modified system functioned well and typing results were supported by partial core sequencing. The following distribution of genotypes was found in 53 hepatitis C virus (HCV) infected Swedish blood donors: genotype 1a (57%), 3 (19%), 1b (13%), and 2b (11%). In six recipients of HCV infected blood identified in a retrospective study, the recipient HCV genotype was identical to donor HCV genotype. Furthermore, in HCV positive couples identical genotype was observed when only one partner had an external risk factor; whereas genotypes were often diverse if both sex partners had parenteral risk factors. Finally, a cluster of hepatitis C cases in a haemodialysis unit was evaluated retrospectively. Eight patients had genotype 1b, two had mixed 1a and 1b, and one had type 1a. The modified HCV genotyping assay was of value in examining different epidemiological situations and can be expanded presumably to include future genotypes.

Different types of heparin in haemodialysis: long-term effects on post-heparin lipases.

Several long-term studies of haemodialysis patients have shown improved serum lipid profile associated with treatment with low molecular weight heparin (LMWH) as compared with unfractionated heparin (UH). This has been attributed to the fact that LMWH produces a less marked acute lipolytic response than UH. However, the information on the differences in long-term effects on tissue releasable lipases is limited. Post-heparin plasma lipase activities were measured at 6, 24 and 48 h after pre-dialysis heparin injections in seven patients on chronic haemodialysis during treatment with UH; these measurements were then repeated 2 and 6 months after treatment was switched to LMWH. The curves plotted from the results can be assumed to reflect the interdialytic lipolytic potential. In the case of lipoprotein lipase this was unchanged 2 months after treatment was switched from UH to LMWH but increased by a mean of 47% after 6 months. In the case of hepatic lipase there was no change in the interdialytic lipolytic potential. Thus, there was a slow increase in tissue releasable lipoprotein lipase stores after treatment was switched from UH to LMWH, probably reflecting a smaller loss of lipoprotein lipase after each LMWH injection. Hepatic lipase, in contrast, was not affected by the type of anticoagulation.

Hepatitis C virus infection in hemodialysis patients in southern Sweden: epidemiological, clinical, and diagnostic aspects.

A prevalence of hepatitis C virus (HCV) antibodies of 12% was found in 276 patients from 11 dialysis units. Between zero and 22% of the patients in the different units were anti-HCV positive. The epidemiology of HCV was studied in two units during a 2 year period by antibody assays and the polymerase chain reaction and correlated with clinical manifestations. Two types of epidemiologic patterns were found that may explain the wide difference of HCV prevalence described in different dialysis units. In one unit there was no evidence of spread within the unit, and the prevalence of HCV was dependent on the status of the patients entering for treatment. In the other unit, a clustering of infected patients could be seen in which 13 of 36 were infected during a 3 year period. Some patients who had not received blood transfusions were among the infected. Hepatitis C infection was the most common explanation for repeated abnormal transferase levels. Most of the HCV-infected patients reacted both for anti-HCV and HCV RNA. HCV RNA was in general detected earlier than anti-HCV seroconversion. Among 20 HCV RNA-positive serum samples that were anti-HCV ELISA-positive 18 had indeterminate and two negative reactions by immunoblot (RIBA 2). Thus the RIBA 2 test should be used with caution as a confirmatory antibody test in this group of patients.

Reduction of albuminuria after angiotensin converting enzyme inhibition in various renal disorders.

The urinary albumin excretion measured by the albumin creatinine clearance ratio (Calb/Ccreat) and the mean supine arterial blood pressure (MAP) were studied before the start of ACE inhibition, at the start and during up to 1 year of ACE inhibition with Captopril or Enalapril in 35 patients with various chronic proteinuric renal disorders with or without renal failure, arterial hypertension and nephrotic syndrome. Before the start of ACE inhibition mean Calb/Ccreat, MAP, s-albumin and s-creatinine did not change. During ACE inhibition the Calb/Ccreat was reduced from 75% (p less than 0.05) in patients with minimal albuminuria to 41% (p less than 0.005) in patients with extensive albuminuria. Average reduction of albuminuria was 44% at one year's observation time. Serum albumin increased 9% (p less than 0.05), serum creatinine did not change significantly and MAP showed a slight, not uniformly significant decrease. The reduction of Calb/Ccreat was of the same order in the different renal disorders studied and was independent of the renal function, presence or absence of nephrotic syndrome and treatment with antihypertensive or immunosuppressive drugs. The decrease in Calb/Ccreat during ACE inhibition was related to the reduction in MAP at most time intervals, but Calb/Ccreat decreased also when MAP was unchanged or increased. Thus the decrease in Calb/Ccreat during ACE inhibition does not only seem to be a consequence of a decrease in the systemic arterial blood pressure but reasonably also due to changes in the intra-renal hemodynamics and most probably a decrease in the glomerular capillary pressure.

Niridazole as an adjunct to "conventional" immunosuppression in kidney allograft transplantation. Long-term follow up.

To assess the value of niridazole as adjuvant immunosuppressant to conventional steroid and azathioprine therapy, a prospective randomized clinical study in 26 cadaver kidney recipients had been performed. No beneficial effect was observed on the kidney graft survival with the addition of niridazole. Neither was there any additional immunosuppressive action demonstrated in the serum of the patients in this group. On the basis of our limited clinical experience niridazole can not be recommended as an adjunct agent for kidney graft recipients.

Identification of HLA antigens in familial and non-familial epidermodysplasia verruciformis.

The distribution of HLA specificities was studied in 7 non-familial cases of epidermodysplasia verruciformis (EV) and in 5 cases from one family. In the non-familial cases, six antigens of locus A (2, 3, 9, 10, 24, 26) and eight antigens of locus B (7, 15, 27, 35, 37, 38, 40, 41) were found. All 5 cases of familial EV possessed 26,5 haplotype, however, 6 of the remaining 12 healthy family members inherited the same haplotype. There is no association of EV with HLA-A and B antigens. However, the defect of cell-mediated immunity, present in all EV cases, may indicate the association of the disease with other major histocompatibility products (i.e. loci on immune response genes).

Manganese content of large-volume parenteral solutions and of nutrient additives.

Manganese (Mn) was analyzed by flameless atomic absorption spectrophotometry in a variety of commercially produced solutions and additives commonly used in total parenteral nutrition (TPN). The amount of Mn in preparations tested varied among manufacturers and among lots. It was generally present in very small amounts with amino acid preparations supplying the major portion in the TPN formulas. Among amino acid solutions, Aminosyn 10% had the highest Mn content (5.2-17.0 micrograms/liter) with Veinamine 8%, FreAmine II, 8.5%, Travasol 10%, and Nephramine having less than 6.7 micrograms/liter. Other large volume parenterals contained appreciably less Mn, eg, Dextrose 50% had 0.64-2.5 micrograms/liter. Some of the additives were high in Mn, eg, potassium phosphate--280 micrograms/liter, magnesium sulfate 50%--up to 225 micrograms/liter, and Berocca C--245.8 micrograms/liter but their actual contributions to daily TPN intake was no more than 3.3 micrograms. The calculated Mn content in TPN formulas with varying source materials ranged from 8.07-21.75 micrograms per total daily volume. These values agreed with those obtained from analysis of actual TPN solutions. The values for 10% Intralipid and 20% Liposyn were 0.5 and 3.0 micrograms/liter, respectively.

Denervated and intact kidney responses to exercise in the dog.

In conscious female dogs exercise-induced changes in the function of the innervated and denervated kidney were studied by clearance techniques. The animals were prepared for experiments by chronic unilateral renal denervation and surgical division of the urinary bladder to enable separate urine collection from each kidney. A 20-min run on a treadmill at a speed of 2.6 m/s significantly decreased urine flow, osmolar clearance, sodium excretion, as well as clearances of exogenous creatinine and p-aminohippurate in the denervated kidney only. In dogs running at 3.6 m/s renal hemodynamics decreased significantly and similarly for both kidneys, whereas the fall in renal excretion was virtually limited to the denervated kidney. As glomerular filtration rate (GFR) was falling during exercise, sodium excretion per 100 ml GFR tended to increase in the innervated kidney, in contrast to an expected slight fall on the denervated side. This indicated a defect of tubular sodium reabsorption of the innervated kidney. On the whole, the data do not support an important mediatory role of renal nerves in the mechanism of renal function changes during exercise.