[Analgesics consumption and analgesic-induced nephropathies in West Germany].
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Biomedical subjects
Publications and source records attributed to G Offermann.
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Out of 80 kidney graft recipients treated with cyclosporin A and low dose steroids 19 (23.8%) developed herpes virus infection and from these 15 (18.8%) herpetic stomatitis. Evaluation of enhancing factors for herpetic stomatitis suggested a role of cyclosporin A rather than of steroids and a probable relation to preceding CMV infection. Acyclovir treatment was effective on the course of stomatitis and pain in 12 of the 15 patients. No serious side effects were observed. Leukopenia as a possible hazard was discussed.
In our haemodialysis centre patients (n = 144), we compared 48 aspects of morbidity in patients with analgesic-associated nephropathy (AAN) and patients with other kidney diseases to determine the presence of characteristic diagnostic features of AAN in addition to a history of habitual analgesic intake. The comparison between 48 AAN patients and the control patients revealed statistically significant differences (p less than 0.05) with regard to myocardial infarction (25% vs 7%), angina pectoris (63% vs 32%), atrial fibrillation (21% vs 4%), arteriosclerosis obliterans of the lower extremity (52% vs 33%), anaemia (mean haemoglobin, 8.38 vs 9.16 g/dl), renal osteodystrophy (67% vs 41%), carpal tunnel syndrome (23% vs 7%), peptic ulcers and erosive gastritis (54% vs 23%), colonic diverticula (15% vs 4%), and haemorrhoids (67% vs 28%). AAN patients therefore have significantly higher morbidity with a characteristic pattern than do patients with other renal diseases.
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The indication for digitalis treatment was investigated in a controlled and prospective study lasting 12 months in 110 patients on long-term haemodialysis. In ten patients, digitalis was needed because of tachyarrhythmia due to atrial fibrillation and in five because of recurrent pulmonary edema. In 57 patients receiving digitoxin, therapy was discontinued for 4 to 6 weeks, whereas 13 patients not yet treated with digitalis, received digitoxin for 4 weeks. Without digitoxin, trial fibrillation occurred in 4 patients, while no patient experienced atrial fibrillation with digitoxin (P = 0.002). In 13 patients, radiological findings (heart enlargement, pulmonary congestion) were better with digitoxin than without. Thus digitoxin appeared to be clearly indicated in 29% of the haemodialysed patients. Additionally, digitalis was indicated in 31 patients because of heart enlargement, pulmonary congestion and (or) previous pulmonary edema. Initially, 76% of the patients were receiving digitoxin, whereas, after the investigation, the rate was only 57% (P less than 0.001). The prospective frequency of clinically apparent digitoxin intoxication was low (3%) and so were the overall toxic plasma digitoxin levels (5%). Digitalis should be given deliberately but not restrictively to haemodialysis patients, since atrial fibrillation (13%) and heart failure (50%) are frequent and often concealed.
Evaluation of the efficiency of extracorporeal elimination is rendered difficult by the rebound phenomenon which may occur in plasma concentrations after hemodialysis, hemoperfusion, or plasma exchange. The term clearance, derived from the extraction rate, has the drawback that it is often based on the incompatible terms plasma concentration and blood flow. To avoid these difficulties, clearance may be calculated from kinetics of plasma concentrations. But this approach will lead to an overestimation of the eliminative efficiency, because plasma concentrations may decline faster than tissue levels, which will be indicated by the rebound phenomenon. The rebound is due to a redistribution from tissue into plasma and follows 2-compartment kinetics. However, the amount removed by extracorporeal elimination reflects the redistribution phenomenon and, simultaneously, can be used to evaluate the absolute efficiency. The amount removed can be derived from 1-compartment kinetics if redistribution can be neglected, and from 2-compartment kinetics if a redistribution takes place. The amount removed can also be evaluated using model- independent approaches, which may be applied even if sustained absorption or proliferation must be assumed. According to these approaches, the removed amount is given by graphic extrapolation, and it can be calculated from extracorporeal clearance and from concentrations in the removed fluid, or it can be eluted from the extracorporeal device.
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The effect of repeated plasma exchanges on the steady state kinetics of digoxin (3 patients) and digitoxin (4 patients) was investigated in 7 patients. Plasma exchange was performed 3 times a week for 4 weeks up to 12 exchanges using a hollow fiber membrane. In each exchange, 4000 ml plasma were filtered within 1 to 2 h and replaced by an albumin containing (20 g/l) physiological electrolyte solution. Digoxin and digitoxin concentrations in blood and filtered plasma were measured by radioimmunoassay. The effects due to the amount eliminated by plasma exchange were distinguished from the effects due to hypoalbuminemia. The eliminative effect was confined to the plasma compartment. It resulted in a marginal decrease in the elimination half-life from 1.6 to 1.59 days for digoxin and 4.3 to 4.2 days for digitoxin. Theoretically, it can be calculated that the hypoalbuminemia caused an increase in the volume of distribution from 451 to 497 l (digoxin) and 35 to 50 l (digitoxin) and a further decrease in the elimination half-life from 4.2 to 4.1 days in the case of digitoxin (not digoxin). If given within 2 h prior to plasma exchange, 13 to 50% of the digitoxin dose (not digoxin) was eliminated. Alteration of digoxin and digitoxin dosage during repeated plasma exchanges is not recommended, but drugs should be given after, not before plasma exchange.
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Interest in the therapeutic use of plasma exchange for various diseases is growing. The two different effects of plasma exchange are elimination and activation. The kinetics are linear for elimination by plasma exchange, but not for activation. Plasma exchange is performed intermittently and can be described by intermittent kinetics. According to intermittent kinetics, plasma exchange removes 50% to 75% of a substance in plasma within 1-2 h, corresponding to an elimination half-life of 30-40 min. Hybrid kinetics, a mixture of actually intermittent but theoretically continuous elimination by plasma exchange, can however also be applied. Hybrid kinetics are more convenient and more reliable than intermittent kinetics. This is because hybrid kinetics are based solely on the concentrations before each plasma exchange; hybrid kinetics also reflect removal from the entire body and not just from the plasma compartment. According to hybrid kinetics, the amount of a substance in the body removed within 3-4 days is 50% of the difference between the initial and the final plasma concentration, depending on the intensity of plasma exchange. The intensity may well contribute at least in part to the beneficial effect of plasma exchange in various diseases.
Within 30 months the diagnosis of drug-induced acute interstitial nephritis was made in ten patients with acute onset of renal failure of clinically unknown cause. Allergenic substances were discovered to be antibiotics, pyrazol and indol derivatives, piromidic acid and chlorazanil. In contrast to the known course of methicillin nephritis the clinical signs were undramatic. Non-oliguric renal failure predominated, sometimes with leucocyturia, microhaematuria and moderate proteinuria. Intermittent haemodialysis was necessary in half the cases. Renal function developed favourably without further specific treatment, however, plasma creatinine did not return to normal levels in most cases. Percutaneous renal biopsy was the definitive diagnostic step. Indications for biopsy in cases of unclear acute renal failure should thus be handled liberally in order to prevent continued drug exposure with the danger of irreversible renal failure.
The important role of immunological factors, HLA typing and pretransplant blood transfusion on improved kidney graft survival is well established. Additionally, graft survival depends on risk factors such as diabetes and age of the recipient. The effect of other clinical risk factors on graft survival was evaluated in 187 patients who received kidney transplants at our centre between 1970 and 1981. Graft survival according to the life table method and statistical analysis according to the logrank test revealed 4 main risk factors. Graft survival is significantly lower in type I diabetics and analgesic nephropathy, whereas it is better in hereditary and other renal diseases. Additional risk factors are coronary heart disease and repeated grafting. Time of dialysis before transplantation and age of the recipient showed no detrimental effect on graft survival.
A 35 years old female developed a slowly progressive acute renal failure after surgical drainage of a pancreatic abscess. Due to the uncharacteristic course a renal biopsy was performed which revealed a severe obstructive renal oxalosis with concomitant interstitial nephritis. Primary oxalosis was excluded by determination of glyceric and glycolic acid in the urine. Since other preconditions for increased oxalate formation were not present it was considered as an adverse reaction to the parenteral application of xylitol. During 4 weeks of total parenteral nutrition the patient received this sugar alcohol in a dose of 3.0 g/kg/day (total dose 4480 g). In recognition of preceding autopsy studies and recent experimental investigations on the metabolic pathways from xylitol to oxalate the chances and conditions of renal deposition of calcium oxalate after administration of xylitol are discussed.
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It is the aim of this paper to review in tabulated form the supplementary dose of drugs required after hemodialysis and to discuss the basic pharmacokinetics of these drugs in the presence of reduced renal function. This review is intended to point out practical aspects of clinical nephrology, It refers to data available from the literature. The descriptions of pharmacokinetics focus on the amount of drug in the body. The fraction of this amount removed by dialysis is replaced by the supplementary dose to maintain effective drug action. The rebound phenomenon affecting plasma drug levels after dialysis renders the calculation of the supplementary dose difficult. Linear extrapolation from plasma drug concentrations measured 6-12 h or more after dialysis may offer a solution to this problem.
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