Incidence of stroke among chronic hemodialysis patients with nonrheumatic atrial fibrillation.

In general, nonrheumatic atrial fibrillation is associated with a high risk of stroke. However, its impact on stroke in the setting of chronic hemodialysis treatment is insufficiently addressed in the literature. We assessed the incidence of stroke among 430 chronic hemodialysis patients and the impact of atrial fibrillation and various other potential risk factors on stroke in a retrospective study covering 1,111.16 patient-years. The overall incidence of stroke was 3.78/100 patient-years. Among patients with chronic atrial fibrillation without any antithrombotic therapy besides regular dialysis anticoagulation, the stroke incidence was 1.0/100 patient-years and did not differ statistically significantly from the rate among patients without this arrhythmia, in whom the incidence was 2.8/100 patient-years (p = 0.220). Conversely, the overall rate of stroke incidence per 100 patient-years was statistically significantly higher in patients with diabetic nephropathy (6.46, p = 0.0036), age > 65 years (5.90, p = 0.0001), moderate to severe hypertension (6.8, p = 0.0017), weight gain of > 2 kg between dialyses as a marker of poor patient compliance (6.47, p = 0.0433), and antithrombotic therapy with salicylates or warfarin (8.33, p = 0.0002), as compared with corresponding groups without these risk factors. Our data suggest that in contrast to other risk factors nonrheumatic atrial fibrillation in itself is not associated with an increased risk of stroke in patients on maintenance hemodialysis treatment.

Prevalence of preterminal pulmonary thromboembolism among patients on maintenance hemodialysis treatment before and after introduction of recombinant erythropoietin.

The prevalence of pulmonary thromboembolism at autopsy was assessed in a retrospective study of a cohort of 185 patients undergoing maintenance hemodialysis treatment who died in the last decade. The overall frequency of thromboembolism was 12.43% in the dialysis population, which statistically was significantly less than in a control group of 8,051 nondialysis patients (21.77%; P = 0.0023). Moreover, pulmonary thromboembolism was less frequently fatal or contributing to death in the dialysis group than in the control group (P = 0.039). The prevalence of pulmonary thromboembolism in the dialysis group remained statistically unchanged over the 10-year period and was independent of a steady increase in the percentage of patients receiving recombinant erythropoietin therapy and the average hematocrit values. The occurrence of preterminal pulmonary thromboembolism was associated with a shorter period since onset of hemodialysis treatment and with infection as cause of death (P = 0. 031; P = 0.029, respectively). No statistically significant influence of the type of basic renal disease, type of dialysis anticoagulation, or dialysis access could be found. Our data suggest that, at least in the preterminal stage, the introduction of recombinant erythropoietin within the last decade had no substantial influence on the prevalence of pulmonary thromboembolism.

Inappropriately high plasma leptin levels in obese haemodialysis patients can be reduced by high flux haemodialysis and haemodiafiltration.

1. Blood leptin levels are increased in obese subjects and seem to play a major role in the hypothalamic regulation of appetite and energy expenditure. 2. We measured plasma leptin levels in a cohort of 46 patients on maintenance haemodialysis treatment and 26 control subjects. 3. Higher body mass indices were associated with higher plasma leptin levels in both groups. 4. The increase was more pronounced in the dialysis group than in the control group (P = 0.001), leading to inappropriately high plasma levels. 5. Haemodialysis with low flux cellulosic dialysers did not result in a decrease in plasma levels, while dialysis with high flux dialysers and haemodiafiltration led to a substantial reduction of the initial value to 76.95 +/- 14.89% (P = 0.013) and 62.90 +/- 24.94% (P = 0.001) respectively. 6. Our data suggest that high flux dialysis membranes can decrease plasma leptin levels and that inappropriately high plasma leptin levels may play a role in the nutrition of haemodialysis patients.

MDR1 gene expression in lymphocytes of patients with renal transplants.

The MDR1 gene, a multidrug resistance gene, codes for P-glycoprotein which pumps hydrophobic drugs out of the cells. Since cyclosporins also bind to P-glycoprotein and might be pumped by this transmembrane protein, we determined the expression of the MDR1 gene in the lymphocytes of 32 patients with renal transplants. MDR1 RNA expression of lymphocytes was measured by slot blot analysis and compared to the expression of drug-sensitive KB-3-1 cells and multidrug-resistant KB-8-5 cells. MDR1 RNA expression was detected in the lymphocytes of 9 (28%) patients, whereas no expression was seen in the remaining 23 patients. No association between MDR1 RNA expression and transplant function or hematological parameters was observed. However, none of the 6 patients who had transplants for more than 40 months expressed the MDR1 gene in their lymphocytes. In conclusion, expression of the MDR1 gene does occur in lymphocytes of patients with renal transplants and might reduce the immunosuppressive efficacy of cyclosporins through enhanced efflux of cyclosporins.

Impaired erythropoietin responsiveness in anaemic rheumatoid arthritis patients: potential relation to immune mechanisms.

1. Serum levels of erythropoietin and the immune parameters tumour necrosis factor-alpha, soluble interleukin-2 receptor, interleukin-2, interleukin-6 and interferon-gamma were measured in patients with rheumatoid arthritis. 2. Out of 69 patients, 44 had anaemia with serum haemoglobin concentrations of 10.8 (SD 1.2) g/dl. In these patients erythropoietin levels were significantly higher than in non-anaemic patients [51.97 (SD 23.9) versus 26.06 (SD 11.9) m-units/ml; P < 0.0001; control patients: 18.1 (SD 13.8) m-units/ml]. Mean soluble interleukin-2 receptor activity was elevated in all patients with rheumatoid arthritis [1324 (SD 715) units/ml; control patients: 480 (SD 75) units/ml; P < 0.001] and was significantly higher in the anaemic group than in the non-anaemic group [1562 (SD 662) versus 696 (SD 402) units/ml; P < 0.0001]. The serum activity of soluble interleukin-2 receptor showed an inverse correlation with haemoglobin (r = 0.79; P < 0.0001) and a positive correlation with erythropoietin (r = 0.70, P < 0.0001). 3. Elevated serum tumour necrosis factor-alpha levels were found in 19 anaemic patients [20.6 (SD 9.1) pg/ml]. Concentrations of tumour necrosis factor-alpha in serum showed an inverse correlation with haemoglobin (r = 0.57, P < 0.001) and a positive correlation with erythropoietin (r = 0.46, P < 0.05). Interleukin-6 was detected in seven anaemic patients [21 (SD 14) pg/ml] and interleukin-2 activity in three anaemic patients (12, 16 and 14 units/ml, respectively). Interferon-gamma was not detected in any of the patients investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Value of serum soluble tumour necrosis factor concentrations in the diagnosis and prognosis of renal graft rejection.

Up to the present the histological diagnosis of rejection through biopsy is still the only possibility for a definite rejection diagnosis. We searched for a reliable non-invasive marker of renal graft rejection. By means of a highly sensitive enzyme-linked immunosorbent assay we investigated the changes in the concentration of serum soluble TNF receptor in kidney graft recipients with different clinical courses according to their graft tolerance. sTNF-R in 19 patients with stable graft function (5.3 +/- 3.2 ng/ml) did not differ significantly from those detected in 22 healty volunteers (4.1 +/- 2.2 ng/ml). In contrast 17 patients suffering from acute graft rejection showed highly significantly increases (23 +/- 8.3 ng/ml, P < 0.0001). These elevated concentrations returned to prerejection rejection values after a 3-day anti-rejection therapy with high-dose methylprednisolone. In 18 patients with an irreversible, chronic kidney graft rejection we could demonstrate significantly increased sTNF-R values (20 +/- 7.9 ng/ml); eight of those patients did not reflect on the anti-rejection therapy, so that the elevated concentrations remained even after the administration of high-dose corticosteroids and ATG. Additionally we found soluble TNF receptor concentrations to be increased earlier than other commonly used biochemical parameters such as creatinine. Soluble TNF-R also proved to be useful for the differentiation of cyclosporin nephrotoxicity. Therefore we believe that the soluble TNF-R and its concentration course may be of diagnostic and prognostic value in kidney graft rejection, as it supports the diagnosis of transplant rejection, indicates the rejection event very early, and reflects the response to anti-rejection therapy.

Plasma protein adsorption to hemodialysis membranes: studies in an in vitro model.

Upon interaction of whole blood with foreign materials, heterogeneous protein films are deposited onto the artificial surface (eg, hemodialysis membranes). The composition of these protein films subsequently affects various processes, eg, thrombogenesis or activation of the complement system. We developed an in vitro model with which we can identify and study proteins interacting with capillaries during hemodialysis. Using this model we studied the cuprophane dialyzer GFS 120 (CP) and the polymethylmetacrylate membrane Filtryzer B2-1.2 (PMMA). Heparinized whole blood from healthy young volunteers was dialyzed on an extracorporeal dialysis machine. After the dialysis procedure the adsorbed material was eluted from the hemodialysis membranes by different eluants and subsequently analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. A number of proteins could be identified in the eluates of both membrane types. Interestingly, platelet glycoproteins could only be found in PMMA eluates. Albumin, IgG, and antithrombin III were mainly present in the cuprophane eluates. Fibrinogen was demonstrable in all eluates, but in relatively low amounts, and the protein was significantly degraded. Degradation products of antithrombin III and complement factor 3 could also be identified. The process causing the degradation has not yet been identified, but may be due to proteases released from damaged cells.

Plasma levels of endothelin in chronic renal failure and after renal transplantation: impact on hypertension and cyclosporin A-associated nephrotoxicity.

1. Plasma levels of endothelin were measured in 30 patients with chronic renal failure, 32 patients on chronic haemodialysis treatment and 25 renal graft recipients with stable renal graft function. 2. In patients with chronic renal failure as well as in patients on regular haemodialysis treatment, mean plasma levels of endothelin were significantly increased (4.59 +/- 2.09 pg/ml, 10.08 +/- 3.12 pg/ml, respectively) when compared with normal subjects (1.88 +/- 0.6 pg/ml, P less than 0.01, P less than 0.001, respectively). 3. In the group with chronic renal failure a positive correlation between the plasma level of endothelin and the plasma concentration of creatinine was observed (P less than 0.003). 4. Renal graft recipients on cyclosporin A with stable renal graft function had a normal plasma level of endothelin suggesting that cyclosporin A nephrotoxicity is not mediated by endothelin. 5. Hypertensive patients with chronic renal failure or on regular haemodialysis and hypertensive renal graft recipients did not differ from the corresponding normotensive population with regard to the plasma level of endothelin, demonstrating that an increased plasma level of endothelin does not play a major role in the pathogenesis of renal hypertension.

Predictive value of thallium-201-dipyridamole myocardial stress scintigraphy in chronic hemodialysis patients and transplant recipients.

The prognostic impact of thallium(Tl)-201-dipyridamole (DPM) stress and redistribution scintigraphy done in 36 patients on chronic hemodialysis (HD) and in 23 renal transplant recipients (TRs) was evaluated according to cardiovascular complications and survival in a follow-up period of six years. Though symptomatic ischemic heart disease (IHD) was present in 33% of HD patients and in 17% of TRs, 50% and 39%, respectively, had Tl-201 findings indicative of IHD. The duration of HD treatment was similar for patients with an abnormal or normal scintigraphic finding. Abnormal Tl-201 results were seen more frequently in older patients. During follow-up, 27 of 36 HD-patients died, 16 had an abnormal and 11 a normal Tl-201-DPM finding; cardiovascular complications were the cause of death in 88% and 18% of these patients, respectively. Thus the incidence of death from fatal cardiac events was 12% per year at risk for the former and 1.9% per year at risk for the latter. In TRs survival was not different for patients with an abnormal or normal Tl-201 finding (56% vs. 64%). However, fatal or nonfatal cardiovascular events were seen more frequently in patients with an abnormal Tl-201 results (78% versus 7%; p less than 0.0001). Stepwise logistic analysis and survival analysis demonstrated Tl-201-DPM stress/redistribution scintigraphy to be the only predictor for identifying patients at increased risk for cardiovascular events. In patients with abnormal Tl-201-DPM scintigraphy subsequent survival was extended for symptomatic patients as compared to asymptomatic ones )30.3 +/- 21.6 versus 22.0 +/- 17.3 months; p less than 0.008).

Decreased postheparin lipolytic activity in renal transplant recipients with cyclosporin A.

The patterns of hyperlipidemia in renal transplant recipients (RTRs) are more variable than in the uremic state, showing increases in both very low-density lipoprotein (VLDL) and low density lipoprotein (LDL). This has been attributed, at least in part, to immunosuppressive therapy, especially to treatment with corticosteroids. Postheparin lipolytic activity (PHLA) was determined in 28 RTRs. Sixteen patients presenting with hyperlipidemia comprised group A, who were aged 49.8 +/- 13.5 years, and had a cholesterol of 8.24 +/- 1.86 mmol/liter, triglycerides of 6.02 +/- 3.33 mmol/liter. Twelve patients presenting cholesterol and triglyceride values within the normal range were in group B, and were aged 48.6 +/- 13.3 years. All RTRs received cyclosporin A (CsA) twice daily orally, which were divided in two equal doses and adjusted to provide CsA blood trough levels (RIA) in a range of 250 to 350 ng/ml. Twenty-one RTRs were additionally treated by alternate-day corticosteroids, whereas seven patients had CsA on their sole immunosuppressive agent. PHLA (mumol free fatty acids/ml/hr, given 10 and 20 min after 100 U/heparin kg body wt intravenously) was commonly reduced in RTRs (group A at 10/20 min: 5.6 +/- 1.1/5.26 +/- 1.2; group B: 8.26 +/- 2.91/8.38 +/- 3.44) as compared to the values obtained in healthy controls (15.3 +/- 2.9/17.2 +/- 5.0). This was mainly due to a reduction of the activity of the hepatic triglyceride lipase, and to a minor extent to a reduced activity of peripheral lipoprotein lipase. There was no statistically significant difference of PHLA in RTRs with or without corticosteroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-interleukin-1 alpha autoantibodies in hemodialysis patients.

IL-1 activity is increased in hemodialysis patients and interest has recently been focused on IL-1 antagonism in various clinical settings. We studied the presence of anti-IL-1 alpha autoantibodies in sera from 49 hemodialysis patients, 159 kidney graft recipients and 89 chronic renal failure patients without renal replacement therapy. Within the three month study period 32.6% of the hemodialysis patients were found to present with anti-IL-1 alpha autoantibodies, in contrast to 5.6% of kidney graft recipients, 8.9% of chronic renal failure patients, and only 1.4% of healthy subjects. The presence of these autoantibodies was neither associated with primary kidney disease nor with the type of dialysis membrane we used. In addition, in antibody positive patients a pronounced increase of IL-1 alpha serum levels within a dialysis session from 14.8 +/- 4.7 pg/ml to 26.4 +/- 11.2 pg/ml (P less than 0.0005) was observed, contrasting to the more even increase from 14.1 +/- 3.1 pg/ml to 19.3 +/- 12.7 pg/ml (P less than 0.05) in the antibody negative group. Neither clinical symptoms due to adverse effects of IL-1 alpha nor some influence on erythropoiesis mediated by IL-1 alpha could be envisaged. Thus, we believe, that anti-IL-1 alpha autoantibodies, present in high frequency in hemodialysis patients, have a neutralizing effect on IL-1 alpha in these patients.

Serum-erythropoietin concentration during acute cardiogenic pulmonary edema.

Reduced oxygen tension is regarded as the primary physiologic signal for the production of erythropoietin (EPO). There is little information available about early changes of EPO production in man due to severe hypoxia. The purpose of the present study was to examine the time course of EPO in serum of patients with acute cardiogenic pulmonary edema (ACPE). In 29 patients (seventy-five +/- six years, mean age +/- SEM) who were hospitalized within two hours after onset of symptoms of ACPE, serum EPO concentrations were monitored for up to seventy-two hours. At the moment of admission all patients showed significantly increased EPO concentrations of 121 +/- 64 mU/mL (mean +/- SEM) compared with a healthy population (15-35 mU/mL). Twenty-three patients who recovered within thirty minutes (group A) exhibited a quick return of their EPO serum levels to normal. The remaining 6 patients (group B) had a protracted clinical course and their EPO concentration showed a further increase up to the end of the observation period. The comparative monitoring of concentrations of alpha-1-proteinase inhibitor, antithrombin III, C-reactive protein, fibronectin, hapotoglobin, and transerrin in serum and plasma revealed no significant changes. Thus a major contribution of fluid shifts into or from the intravascular compartment to the observed changes in EPO concentration seems to be unlikely. The data suggest that the production and release of EPO in the kidneys due to altered oxygen delivery is a fast-responding mechanism.

Utilization of tyrosine dipeptides and acetyltyrosine in normal and uremic humans.

The impact of renal failure on the elimination and hydrolysis of three sources of tyrosine for parenteral nutrition, the dipeptides alanyltyrosine (Ala-Tyr), glycyltyrosine (Gly-Tyr), and N-acetyltyrosine (NAc-Tyr) was investigated in eight patients on regular hemodialysis therapy (HD) and seven healthy controls (CON). In CON, whole body clearance (Ctot) of Ala-Tyr (3,169 +/- 198 ml/min) was higher than Gly-Tyr (1,781 +/- 184, P less than 0.001), and both exceeded NAc-Tyr (284 +/- 24, P less than 0.001). In HD, Ctot of Ala-Tyr was not different from CON, but Ctot of Gly-Tyr (858 +/- 73, P less than 0.001) and NAc-Tyr (129 +/- 30, P less than 0.02) was decreased. The rise in plasma levels of constituent amino acids was higher in Ala-Tyr vs. Gly-Tyr (P less than 0.01). In HD, the pattern was similar, although the increase in Tyr was less than in CON. Plasma Tyr did not increase with NAc-Tyr in either group. Urinary loss of peptides was neglible, but 60% of NAc-Tyr infused was excreted by CON. The half-life of peptides incubated in CON and HD plasma was unchanged for Ala-Tyr (12.3 +/- 0.9 vs. 14.6 +/- 1.9 min) and prolonged for Gly-Tyr in HD (101.7 +/- 4.9 vs. 131.3 +/- 12, P less than 0.05). Thus renal failure does not impair Ala-Tyr disposal and delays Gly-Tyr utilization. These differential effects on peptide assimilation underscore the importance of peptide structure on metabolism. Both peptides, but not NAc-Tyr, may serve as a nutritional substrate in renal failure patients.

[Beta-N-acetylglucosaminidase (beta-NAG) as a parameter in the diagnosis and evaluation of primary glomerular and tubulointerstitial kidney diseases]. / Beta-N-Acetylglucosaminidase (beta-NAG) als Parameter in der Diagnose und Bewertung von primär glomerulären und primär tubulointerstitiellen Nierenerkrankungen.

beta-N-acetylglucosaminidase (beta-NAG) and beta 2-microglobulin were assessed in two cohorts of patients with glomerular or tubulointerstitial diseases respectively. While beta-NAG activities did not differ statistically significantly between both groups, beta 2-microglobulin excretion was statistically highly significantly increased in the setting of tubulointerstitial diseases. On the whole mean beta-NAG activity at 37 degrees C and beta 2-microglobulin urinary excretion were elevated in both groups, when compared to normal controls. Increased beta-NAG activities above 10 U/g creatinine were associated with a marked increase of creatinine serum levels within 6 months in both, patients with glomerular and tubulointerstitial basic renal diseases. beta-NAG and beta 2-microglobulin are useful tools in diagnosis and assessment of renal diseases elucidating different aspects.

Progression of renal insufficiency in analgesic nephropathy: impact of continuous drug abuse.

Twenty-three patients with analgesic nephropathy and apparent cessation of drug abuse were tested for blood acetaminophen and salicylate on the occasion of routine renal control examinations. In 12 patients (mean creatinine level 2.74 +/- 1.09 mg/dl) no deterioration of renal function was noted within a 1-year observation period (Group 1). In 11 patients a significant progression of renal insufficiency was observed (mean creatinine level rose from 3.86 +/- 1.06 to 6.40 +/- 3.18 mg/dl within the same observation period; Group 2). Blood tests for acetaminophen and salicylate were positive in 2 patients of Group 1 and in 9 patients of Group 2 (chi 2 = 7.326), p less than 0.01). Our data emphasize the importance of a continuous analgesic abuse hidden from the medical staff with regard to the progression of renal insufficiency in analgesic nephropathy.