The analgesic problem in the Federal Republic of Germany: analgesic consumption, frequency of analgesic nephropathy and regional differences.

The recent withdrawal of phenacetin from the pharmaceutical market in the FRG has stimulated the discussion of the extent of analgesic abuse and analgesic nephropathy (AN). Data from wholesale statistics, given here, revealed in the FRG population a high yearly per-capita consumption of analgesics (18.2 g), mostly used in mixed compounds. According to standardized data, the FRG ranks first among the north European countries. We suggest that the prevalence data given from the EDTA-registry (4.6% of the endstage renal population) underestimates the real extent of AN. AN in the FRG shows a north-to-south decline and is most prevalent in northern areas and West Berlin. It is assumed that the analgesic dilemma in the FRG is identical to the dilemma in Switzerland and Belgium.

Effect of plasma protein binding, volume of distribution and molecular weight on the fraction of drugs eliminated by hemodialysis.

The correlation between plasma protein binding, the volume of distribution, molecular weight, and percentage removed by hemodialysis was investigated in 89 drugs using information available in the literature. The correlation was significantly linear between dialyzability and plasma protein binding, as well as with the reciprocal volume of distribution. This is in agreement with the theoretical deduction of dialyzability from diffusion and convection kinetics. Multiple linear regression analysis revealed that only 27% of the variance in dialyzability could be explained by plasma protein binding (17%), the volume of distribution (6%), and the molecular weight (4%) of the drugs. Therefore, the dialyzability of drugs can not be predicted reliably.

Carpal tunnel syndrome: a major complication in long-term hemodialysis patients.

One hundred and forty-five patients on hemodialysis for periods of 1 month to 16 years were examined clinically for carpal tunnel syndrome (CTS). Typical symptoms and clinical manifestations of symptomatic CTS, either unilaterally or in both hands, were detected in 21 of these patients (15%). In contrast to the classic form of CTS, hemodialysis CTS in our patients was frequently accompanied by Raynaud's phenomenon of those digits supplied by the median nerve. A highly significant correlation was established between the incidence of CTS and the duration of dialysis (p less than 0.001). The association of CTS with analgesic nephropathy was significantly higher (52%) than with other kidney diseases (p less than 0.034). Immediate relief of pain was achieved after carpal tunnel release (11 releases) in 8 of the 21 patients. Sensory and motor function was gradually, but often only partially, restored. Unoperated CTS progressed to loss of sensory and motor function within 1 to 4 years after the onset of symptoms. CTS should be considered a major late complication in patients on chronic hemodialysis.

Outcome of patients with ventricular assist devices and acute renal failure requiring renal replacement therapy.

The significance of acute renal failure (ARF) for patients treated with a ventricular assist device (VAD) is uncertain. There is little information on the outcome of patients who require renal replacement therapy during treatment with a VAD. A retrospective review was undertaken to evaluate the impact of renal failure requiring renal replacement therapy on such patients. Studied were 227 patients who were supplied with a VAD at the German Heart Institute Berlin. Fifty-five patients required renal replacement therapy during treatment with a VAD. These were compared with patients not needing renal replacement therapy (ARF and non-ARF groups). Significant differences for the end points of survival, heart transplantation, and discharge from hospital were observed in patients with ARF (p < 0.01). Survival was then analyzed according to indications for treatment with a VAD (bridge to transplantation or cardiac recovery after cardiotomy, transplantation, myocardial infarction, myocarditis, and endocarditis). Survival for bridge-to-transplantation patients was clearly influenced in a negative way by ARF (p < 0.01). For cardiac recovery patients, only a small difference in survival was observed (p = 0.05). We conclude that ARF is a negative predictor for bridge-to-transplantation patients. For cardiac recovery patients the impact of ARF on survival is marginally significant.

Effect of dialyzer membranes on in vitro generation of eicosanoids.

Eicosanoids are potent substances released from blood cells after contact with foreign materials. Eicosanoid generation, in addition to complement fragment formation, may be a valuable indicator of the biocompatibility of dialyzer membranes. In the present in vitro study, eicosanoid generation induced by several different flat dialyzer membranes [polyacrylonitrile (PAN), cuprammonium cellulose (CC), and polycarbonate (PC)] was evaluated and compared using blood from non-uremic healthy volunteers. Generation of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was greatest with PC followed by PAN and CC. The formation of C3a des arg with PAN was less than with either CC or PC. Our results suggest that dialyzer membranes affect complement activation and eicosanoid generation differently; biocompatibility as expressed by a low level of complement fragment formation does not necessarily translate into biocompatibility when considering eicosanoid generation.

[Chronic use of analgesics]. / Daten zum chronischen Schmerzmittelgebrauch.

Quantitative aspects of longterm analgesic intake are presented, based on a case-control-study on the relation between regular analgesic intake and endstage renal failure in the area of West Berlin (1984-86). Lifetime analgesic consumption of more than 1000 persons were investigated. A total of 285 longterm analgesic users (185 cases = 35.8%; 100 controls = 19.3%) were detected. An odd ratio of 2.44 (95% CI: 1.77-3.39) was computed. Regular analgesic intake was defined as an intake of at least 15 analgesic doses per month continuously over a period of at least 12 months. 90% of the regular users preferred mixed analgesics compounds, in most cases with the psychotropic additive caffeine.

[Analgesics and laxatives as risk factors for cancer in the efferent urinary tract--results of the Berlin Urothelial Carcinoma Study]. / Analgetika und Laxantien als Risikofaktoren für Krebs der ableitenden Harnwege--Ergebnisse der Berliner Urothelkarzinom-Studie (BUS).

A retrospective case-control study (1990-1995), the Berlin Urothelial Cancer Study (BUS), examined analgesics and laxatives as risks for the induction of urothelial cancer in renal pelvis, ureter and bladder. Especially for renal pelvis cancer could observe substance and dose specific risk of compound analgesics. The analgesic substances Phenacetin, Paracetamol, Acetylsalicylic acid (ASA) and Pyrazolones were assessed. Besides a risk of contact laxatives (chemical or anthranoide ingredients) for urothelial cancer was found, not yet described. The highest risk shows the anthranoide plant Senna. Thus this study confirms the risk of specific analgesic ingredients and found an evidence for a new risk of contact laxatives. As both, analgesics and contact laxatives, are typical OTC--("Over the counter") products, a severe controlling is demanded and for laxatives further studies are needed.

Effect of primary renal disease and risk factors on kidney graft survival.

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.

[Long-term results after kidney transplantation]. / Langzeitergebnisse nach Nierentransplantation.

In this investigation, our own long-term results after kidney transplantation were compared with those in literature, and the influence of recent findings on the survival rate of patients and transplants was analyzed. In 217 kidney transplant patients, the 5 and 9-year-patient survival rate was calculated at 58% and 45% respectively. The 9-year-transplant function rate was 38%. Analogous results can be derived from collective international and European statistics. The long-term patient survival rate after successful transplantation shows better results than comparable statistics of hemodialysis treatment. Analysis of the results fractionated into the years 1970 to 1974, 1975 to 1977 and 1978 to 1981 shows a continuous improvement in the survival rate of patients and transplants. This improvement of results can be attributed to the reduction of surgical complications with increasing experience and particularly to knowledge recently gained in the field of transplantation immunology (compatibility in the HLA-A/B and -DR system, preoperative blood transfusions) and immunosuppression (reduction of steroid doses, supplementary ATG and cyclosporin A medication).

Does captopril reduce renal function in renovascular disease by postglomerular vasodilatation?

In hypertensive patients with bilateral renal artery stenosis (RAS) or RAS of a solitary kidney, reversible decrease of glomerular filtration rate (GFR) or acute renal failure has been observed following captopril administration. Decrease of GFR has been ascribed to preferential efferent vasodilatation. To test this hypothesis, acute changes of mean arterial pressure (MAP), renal plasma flow (RPF), GFR, plasma renin activity (PRA) and PGE2-excretion after 50 mg captopril orally were measured in post-transplant hypertensives with and without transplant renal artery stenosis (TRAS) during treatment with diuretics. The fall in MAP was similar in both groups; RPF did not change significantly; GFR decreased from 58 +/- 14 (s.d.) to 49 +/- 14 ml/min (TRAS, n = 8) and from 60 +/- 15 to 50 +/- 16 ml/min (without TRAS, n = 8). There was no evidence of postglomerular dilatation in patients with TRAS, and filtration fraction decreased only in patients without TRAS. Increase of PRA after captopril was not significantly different between the two groups. PGE2-excretion did not change significantly. In one patient with severe TRAS, long term angiotensin converting enzyme (ACE) inhibition and acute normalization of MAP with sodium nitroprusside both induced a comparable decrease of GFR. The results demonstrate that acute postglomerular vasodilatation does not necessarily occur after ACE inhibition in patients with TRAS and a high-renin state.

Future evolution of the ESRD patient population--a perspective for the year 2000.

Renal replacement therapy of the next decade in Europe will be strongly influenced by certain epidemiological developments, which can be observed in some parts of the world since several years. The overall incidence rates of new patients will rise up to 300 pmp per year, the prevalence rates of patients on treatment will exceed 1000 pmp in some European countries as well as in Japan and in the USA. This is due to a more than proportional increase in the acceptance rates for people older than 65, mostly patients with type II diabetes and hypertensive nephropathy. In Europe, the proportion of patients with NIDDM and diabetic nephropathy shows marked regional differences, which may be more or less important for the development of the whole patient population. Since diabetes as well as hypertensive disease are conditions with high risks for non-renal complications, one cannot expect important improvements in patient survival in spite of technical developments in dialysis therapy.

Digoxin dosage in renal insufficiency: impracticality of basing it on the creatinine clearance, body weight and volume of distribution.

Previous dosing schedules for digoxin in renal failure have considered the decrease in the elimination rate constant but not the decrease in the volume of distribution. A dosing schedule based on the creatinine clearance, body weight and volume of distribution has been developed from pharmacokinetic data taken from the literature. Its validity was tested in a clinical study of 35 patients with chronic renal insufficiency not requiring dialysis. The dosing schedule resulted in correct digitalization expressed as a steady state plasma digoxin concentration in the therapeutic range (0.5-2.0 ng/ml) in 25 out of 27 patients (93%). However, of 82 possible candidates for the study, it could not be performed in 47 (57%). The high drop-out rate was mainly due to the complicated dosing schedule and to the difficulty of repeatedly measuring creatinine clearance on a routine basis. Therefore, safe dosing of digoxin in renal insufficiency does not seem to be feasible in practice. Digitoxin may be a better alternative.

Blood pressure in terminal renal failure. Fluid spaces and the renin-angiotensin-system.

Most of the 52 patients on maintenance dialysis investigated in this study suffered from arterial hypertension in spite of efforts to reduce 'dry weight'. In this situation we found that the majority of patients were underweight and that total body water, extracellular volume and blood volume were close to normal when related to reference systems consisting of height and age. Hypertensive patients were not volume expanded as compared to normotensive patients and controls. Plasma renin activity and angiotensin II were elevated in a few patients, with a trend to higher levels in the more hypertensive patients. Various approaches attempting to correlate blood pressure and the respective volume-renin factors did not prove to be conclusive in explaining the maintenance of hypertension in chronic renal failure on the basis of the sodium-renin feedback.

Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment.

Cyclosporin A trough blood levels were unusually low during rifampin treatment in a kidney transplant patient. Simultaneously, acute graft rejection occurred. Pharmacokinetic investigation revealed a rapid turnover of cyclosporin A leading to low blood levels. Cessation of rifampin therapy reversed these changes. Rifampin substantially reduces the bioavailability of cyclosporin A and should not be used in transplant recipients on cyclosporin A.