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Biomedical subjects

Günter Stein

Publications and source records attributed to Günter Stein.

At least 19 recordsLinked to original sources
PubMed2005

Suitability of 5/6 nephrectomy (5/6NX) for the induction of interstitial renal fibrosis in rats--influence of sex, strain, and surgical procedure.

Chronic renal failure (CRF) is a serious clinical problem and currently there are no adequate therapeutic strategies for treatment. Many possible treatment strategies have been tested in rats with CRF induced by subtotal nephrectomy. However, reports in the literature concerning the consequences of this procedure on rat kidney function are contradictory. For instance, such an intervention in male Sprague-Dawley rats apparently initiates the development of interstitial renal fibrosis, while in our similar studies on female Wistar rats (HW) there was minimal renal fibrosis. Therefore, we carried out experiments in adult rats to investigate the long-term consequences of 5/6 nephrectomy (5/6NX) in relation to (1) sex, (2) strain, and (3) two methods of surgical ablation. Ten weeks after 5/6NX, body weight gain, systolic blood pressure, creatinine clearance, and urinary protein were measured, along with renal hydroxyproline concentration determinations to assess the deposition of extracellular matrix. Also, light microscopic investigations were done to characterize renal damage. The functional parameters clearly indicated the development of CRF, while morphologic investigations showed only moderate fibrotic areas containing atrophic tubules and lymphocytic infiltrates. However, 45-60% of glomeruli were sclerotic. In summary, 5/6NX, using either method of partial nephrectomy, induces signs of moderate glomerulonephritis preferentially in female HW rats. Thus 5/6NX in female HW rats can be recommended as a suitable model in the induction of renal fibrosis.

Animals↗
PubMed2005

[Costs of therapy of insulin-treated patients with Diabetes mellitus in Germany. Results of the JEVIN trial].

BACKGROUND AND PURPOSE: Diabetes mellitus, its treatment with oral antidiabetic drugs and insulin, self-monitoring and the development of diabetesrelated long-term complications raise multiple socioeconomic problems. Hence, diabetes is one of the major challenges to modern health care systems. To date, there are only few data analyzing diabetes-related costs. Therefore, it was the aim of this trial to assess the costs of therapy of insulin-treated patients with diabetes mellitus out of a selection-free population over a period of 5 years. PATIENTS AND METHODS: JEVIN (Jena's St. Vincent trial) is a prospective population-based trial of all patients with type 1 and insulin-treated type 2 diabetes mellitus aged 16-60 years and living in the city of Jena, Thuringia, Germany. In addition to parameters of diabetes control (relative hemoglobin A(1c) [= HbA(1c)/mean normal], long-term complications, blood pressure), the costs of therapy in respect of insulin and oral antidiabetic drugs and materials to perform self-monitoring were analyzed in 1999/2000 compared to 1994/95. In 1994/95, 244 patients, in 1999/2000, 291 patients were examined. RESULTS: During the period from 1994/95 to 1999/2000, relative HbA(1c) improved in both patients with type 1 (1.65 +/- 0.35 [n = 127] vs 1.48 +/- 0.30 [n = 114]; p < 0.0001) and insulin-treated type 2 diabetes (1.75 +/- 0.40 [n = 117] vs. 1.47 +/- 0.25 [n = 147]; p < 0.0001). The quality of blood pressure control remained constant. In 1999/2000 the costs per unit insulin for patients with type 1 diabetes were calculated at about 0.078 +/- 0.035 DM, in 1994/95 at 0.075 +/- 0.032 DM (p = 0.873). For patients with type 2 diabetes the costs were calculated at 0.070 +/- 0.032 DM in 1999/2000 and at 0.070 +/- 0.028 DM (p = 0.954) in 1994/95. In 1999/2000, to perform blood glucose self-monitoring the costs were 4.08 +/- 1.39 DM/d for patients with type 1 diabetes and 3.07 +/- 1.36 DM/d for patients with type 2 diabetes. In 1994/95 the costs for patients with type 1 diabetes amounted to 3.56 +/- 1.69 DM/d (p = 0.012), and for patients with insulin-treated type 2 diabetes mellitus to 2.77 +/- 1.66 DM/d (p = 0.138). In 1999/2000 the costs for antihypertensive drugs in 46/114 patients with type 1 diabetes were calculated at about 1.43 +/- 1.10 DM/d. In 1994/95 the costs for 32/127 patients amounted to 1.76 +/- 1.00 DM/d (p = 0.501). For 104/147 patients with insulin-treated type 2 diabetes, the costs of antihypertensive drugs were 2.02 +/- 1.48 DM/d in 1999/2000. In 1994/95 the costs amounted to 1.77 +/- 1.11 DM/d (p = 0.141) for 54/117 patients. In 1994/95 the total costs for patients with type 1 diabetes mellitus were calculated at about 7.10 +/- 2.69 DM/d. In 1999/2000 the costs amounted to 7.70 +/- 2.75 DM/d (p = 0.085). In patients with insulin-treated type 2 diabetes mellitus there was a significant increase in 1999/2000 versus 1994/95 (1994/95: 6.43 +/- 3.16, 1999/2000: 7.57 +/- 3.56 DM/d; p = 0.007). CONCLUSION: Despite a tendency toward an increase in the costs for daily life, the therapy-related costs for patients with type 1 diabetes mellitus were constant in 1999/2000 versus 1994/95. In patients with type 2 diabetes, there was an increase of about 18%. For both patients with type 1 and type 2 diabetes, the costs were substantially higher than calculated in theoretical models.

Administration, Oral↗
PubMed2005

Long-term prognosis of patients after kidney transplantation: a comparison of those with or without diabetes mellitus.

BACKGROUND: Compared with non-diabetic subjects, patients with type 2 diabetes and end-stage renal disease (ESRD) have seldom been selected for renal transplantation. It was the aim of this study to compare the long-term prognoses of the two groups of patients after transplantation and to identify factors associated with allograft rejection. METHODS: In a retrospective analysis, we studied all 333 consecutive patients who received a kidney transplant at our centre since 1992. Mean follow-up in 302 out of 333 patients (91%) was 3.3+/-1.5 (0.1-11.7) years. At the time of transplantation, diabetes mellitus (type 1, n=3; type 2, n=46) was known in 49 patients. RESULTS: Patients with diabetes mellitus were older [patients without diabetes (n=253) vs patients with diabetes (n=49), 52.2+/-12.6 vs 58.8+/-13.1 years, respectively; P=0.002], but they had very good diabetes control [haemoglobin A1c (HbA1c) of patients with diabetes 6.3+/-0.9% vs those without diabetes 5.2+/-1.0%, P=0.03]. Even during their follow-up, patients with diabetes showed a tendency to further improvement (HbA1c for patients with diabetes 5.7+/-0.9% vs those without diabetes 5.5+/-0.9%, P=0.30). At the end of follow-up also, there were no differences between the groups with respect to blood pressure control (patients with diabetes 135.3+/-28.2/79.6+/-17.2 mmHg vs patients without diabetes 130.9+/-28.7/78.8+/-17.1 mmHg, P=0.33/0.78) and renal function (creatinine, 142.9+/-61.6 vs 151.8+/-68.2 micromol/l, P=0.38; glomerular filtration rate, 63.1+/-23.3 vs 59.1+/-24.0 ml/min/1.73 m(2), respectively, P=0.30). In total, 26 patients had acute transplant rejections [eight patients with diabetes (prevalence 16.3%) vs 18 patients without diabeteses (prevalence 7.1%), P=0.11]. In multivariate analysis, the most important parameter associated with the incidence of transplant rejections was the preceding fasting blood glucose (R2=0.044, beta=0.21, P=0.009). All other parameters included in the model (body mass index, time since transplantation, diabetes duration, immunosuppressive therapy, HbA1c and HLA mismatch) revealed no associations. CONCLUSIONS: Following kidney transplantation, the prevalence of rejections in patients with diabetes mellitus is slightly but not significantly higher than in non-diabetic subjects. One of the most important risk factors seems to be fasting blood glucose. Hence, following renal transplantation, treatment strategies should focus not only on optimal immunosuppressive therapy and HLA matching, good HbA1c and blood pressure control, but also on maintaining near-normal fasting blood glucose levels.

Aged↗
PubMed2005

Post-transplant diabetes mellitus: risk factors, frequency of transplant rejections, and long-term prognosis.

BACKGROUND: Estimates of the incidence of new-onset diabetes after renal transplantation vary between 2% and 54%. It was the aim of the present trial to study the prevalence of post-transplant diabetes mellitus (DM), the risk factors, the frequency of transplant rejections, and the long-term prognosis. METHODS: We studied all consecutive patients with endstage renal disease, but without DM who received kidney transplantation at our center since 1992 (n = 253; age, 52.2 +/- 12.6 years; body mass index, 22.0 +/- 7.9 kg/m2). Follow up was 3.3 +/- 1.6 years (range, 0.1-17.7) years. RESULTS: In total, 43/253 patients (17%) developed new-onset DM after transplantation. Patients with new-onset diabetes were significantly older (58.3 +/- 11.4 vs 50.9 +/- 12.5 years; P < 0.01) and had a tendency to a higher body mass index (24.0 +/- 8.5 vs 21.6 +/- 7.8 kg/m2; P = 0.077). There were no differences between the groups in respect of blood pressure control (137.7 +/- 19.0/81.8 +/- 14.2 vs 137.1 +/- 21.9/83.9 +/- 13.1 mmHg; P = 0.89/0.39), glomerular filtration rate (58.0 +/- 28.1 vs 64.1 +/- 22.1 ml/min per 1.73 m2; P = 0.13), steroid dosage (4.5 +/- 1.2 [n = 21] vs 4.6 +/- 2.2 [n = 135] mg/day; P = 0.13), or the frequency and dosage of immunosuppressive drugs such as cyclosporine, tacrolimus, and sirolimus during the follow up. However, more patients with post-transplant diabetes received steroids (83.7% vs 64.3%; P = 0.021) and azathioprine (41.9% vs 24.3%; P = 0.030). Patients with new-onset diabetes had higher serum creatinine values (163.4 +/- 67.9 vs 138.7 +/- 59.5 micromol/l; P = 0.017). The mean hemoglobin (Hb)A1c in patients with DM was 6.28 +/- 1.29% (Tosho HPLC; mean normal, 5.15%). In 18 patients (7.1%) transplant rejections occurred (16 patients without DM [7.6%] vs 2 patients with new-onset DM [4.7%]; P = 0.39). On performing multivariate analysis, the only parameter found to be associated with new-onset DM was the body mass index (R2 = 0.05; beta = 0.23; P = 0.02), and the only factor associated with transplant rejection was fasting blood glucose (R2 = 0.07; beta = 0.28; P = 0.02). None of the other parameters included in the models (age, duration after transplantation, diabetes duration, immunosuppressive therapy, HbA1c, HLA mismatches) showed any associations. CONCLUSIONS: The prevalence of new-onset DM after renal transplantation was 17%. The most important parameter associated with new-onset diabetes was a higher body mass index, and the most important parameter associated with transplant rejection was an elevated fasting blood glucose level. To prevent transplant rejections and to improve patients' outcome, in addition to providing optimal immunosuppressive therapy and HLA matching, good blood pressure control and HbA1c, but also near normal fasting blood glucose levels, should be achieved.

Aged↗
PubMed2005

Smelling renal dysfunction via electronic nose.

The human body odor plays an important role in social communication in various situations, like the olfactory identification of partners and relatives as well as in parents-child interactions. In patients with renal dysfunction the compound of sweat and volatile gases is changed because of the limited ability for removing metabolic products from the blood. The regulation of electrolyte composition and acid-base balance are also altered so that the body odor of these patients may be significantly influenced by these disorders. We show the ability of an electronic nose to detect changes in the human body odor in consequence of renal dysfunction by reducing multivariate sensor signals with principal component analysis to its first and second principal odor component (POC). All healthy subjects could clearly be distinguished from patients with renal failure using quadratic discriminant analysis, whereas a correct classification of 95.2% (98.4% using 1st-3rd POC) of patients between end stage renal failure and chronic renal failure was found. This methodology of analyzing human body odor may also provide new approaches for investigating symptoms of renal failure and for diagnosing other diseases of internal or cutaneous origin.

Biomarkers↗
PubMed2005

Specific measurement of PTH (1-84) in various forms of renal osteodystrophy (ROD) as assessed by bone histomorphometry.

BACKGROUND: Parathyroid hormone (PTH) measurements serve as a noninvasive, diagnostic tool for the assessment of renal osteodystrophy (ROD). Their value has been questioned following reports indicating that all commercially available intact PTH (I-PTH) assays cross-react with amino terminally truncated PTH fragments. Because these fragments can account for 50% of total PTH, their detection will overestimate the true PTH concentration and may lead to diagnostic inaccuracies. The aim of this study was to evaluate the specific Bio-Intact PTH (1-84) Assay (BI-PTH) in patients with various types of ROD confirmed by bone biopsy. METHODS: Bone biopsies were taken from 132 patients with chronic kidney disease (CKD) stages 3 to 5, and quantitative bone histomorphometry was done. Plasma PTH levels were measured using both the BI-PTH and I-PTH assays on an automated analyzer. RESULTS: Patients with CKD stages 3/4 and low turnover skeletal lesions had BI-PTH values (pg/mL, mean +/- SD) of 35 (+/-34) and I-PTH values of 59 (+/- 63). Corresponding values for BI-PTH and I-PTH in those with high turnover lesions were 141 (+/-60) and 221 (+/-106). Patients with CKD stage 5 and low turnover skeletal lesions had BI-PTH and I-PTH levels of 51 (+/-38) and 90 (+/-60), respectively, whereas the corresponding results for BI-PTH and I-PTH in those with high turnover lesions were 237 (+/-214) and 461 (+/-437). The areas under the receiver operating characteristic (ROC) curves for distinguishing low turnover from high turnover lesions were 0.94 for BI-PTH and 0.91 for I-PTH in CKD stages 3/4 and 0.86 for BI-PTH and 0.85 for I-PTH in CKD stage 5. Among all patients, BI-PTH levels are approximately 50% lower than I-PTH levels, but the results of the two assays are correlated highly (R2 = 0.92). CONCLUSION: Plasma PTH measurements using either the BI-PTH or I-PTH assay effectively identify patients with reduced bone turnover and serve to distinguish this subgroup from those with high turnover lesions of renal bone disease. Both assays provide better diagnostic discrimination for this purpose than calculated values for the ratio of PTH (1-84)/amino terminally truncated PTH fragments.

Adult↗
PubMed2005

Advanced glycation end products and the kidney.

Advanced glycation end products (AGEs) are a heterogeneous group of protein and lipids to which sugar residues are covalently bound. AGE formation is increased in situations with hyperglycemia (e.g., diabetes mellitus) and is also stimulated by oxidative stress, for example in uremia. It appears that activation of the renin-angiotensin system may contribute to AGE formation through various mechanisms. Although AGEs could nonspecifically bind to basement membranes and modify their properties, they also induce specific cellular responses including the release of profibrogenic and proinflammatory cytokines by interacting with the receptor for AGE (RAGE). However, additional receptors could bind AGEs, adding to the complexity of this system. The kidney is both: culprit and target of AGEs. A decrease in renal function increases circulating AGE concentrations by reduced clearance as well as increased formation. On the other hand, AGEs are involved in the structural changes of progressive nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy. These effects are most prominent in diabetic nephropathy, but they also contribute to renal pathophysiology in other nondiabetic renal diseases. Interference with AGE formation has therapeutic potential for preventing the progression of chronic renal diseases, as shown from data of animal experiments and, more recently, the first clinical trials.

Animals↗
PubMed2005

Advanced glycation end products: a possible link to angiotensin in an animal model.

Advanced glycation end products (AGEs) have been associated with progressive vascular and renal damage in a variety of pathological conditions such as renal failure and diabetes mellitus. The formation of AGEs is generally attributed to increased oxidative and carbonyl stress or hyperglycemia. Activation of the cellular receptor of AGE (RAGE) leads to subsequent cellular activation and proinflammatory responses. Angiotensin (Ang) produces cellular oxidative stress and similarly promotes end organ damage via its type 1 receptor. We investigated the interrelation between these two systems in a new transgenic rat (TGR) model with Ang II-dependent hypertension and renal damage and in nontransgenic controls. TGR showed increased systolic blood pressure (approximately 210 mmHg), proteinuria, and increased renal collagen I mRNA expression compared with normotensive nontransgenic controls. Immunohistochemical staining of kidney sections showed colocalization for Nepsilon-carboxy(methyl)lysine, RAGE, and NF-kappaB in TGR glomeruli. These features were absent in nontransgenic controls. Our observations suggest a possible link between Ang II-dependent end-organ damage and the AGE/RAGE axis in vivo. TGRs provide an excellent model to study the interrelation between the renin-angiotensin system and the AGE/RAGE axis in promoting cardiovascular end-organ damage, which would otherwise not be possible in humans.

Angiotensinogen↗
PubMed2004

The advanced glycation end product pentosidine correlates to IL-6 and other relevant inflammatory markers in rheumatoid arthritis.

OBJECTIVE: Oxidative stress and inflammatory processes accelerate the formation of advanced glycation end products (AGE), e.g. of pentosidine. The aim of this study was to investigate the relationships between levels of pentosidine in serum and synovial fluid, proinflammatory cytokines, other markers of inflammatory activity, and the state of radiologically visible bone destruction in patients with rheumatoid arthritis (RA). OBJECTIVES: One hundred thirty-three nondiabetic RA patients and 56 age-matched, healthy subjects were included. Serum and synovial fluid pentosidine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor levels were determined. In 30 patients, the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha and the soluble receptors sIL-2R, sIL-6R, sTNF-alpha, and RI/RII were also measured. RESULTS: Serum levels of pentosidine were on average significantly higher in RA patients than in healthy subjects and correlated significantly to ESR, CRP, and serum levels of IL-6. Serum and synovial fluid pentosidine did not show any differences. Rheumatoid factor-positive RA patients had higher pentosidine levels in the synovial fluid than rheumatoid factor-negative patients. Correlations could not be found between pentosidine and the other cytokines or cytokine receptors measured. CONCLUSION: The binding of AGE on cell receptors induces activation of nuclear factor kappa B, resulting in enhanced synthesis of proinflammatory cytokines. Moreover, AGE generation may also lead to the formation of new, immunologically relevant epitopes at synovial proteins. Both mechanisms could contribute to initiation and perpetuation of the inflammatory and destructive processes in RA.

Arginine↗
PubMed2004

[A structured treatment and educational program for patients with type 2 diabetes mellitus, insulin therapy and impaired cognitive function (DikoL)].

BACKGROUND AND PURPOSE: More than 50% of patients with type-2 diabetes mellitus and impaired cognitive function are overtaxed with some topics of established structured treatment and teaching programs for patients with insulin therapy. This leads to substantial deficits in respect of the patients' ability of diabetes self-management (insulin injections, self-monitoring) and the need for help by relatives and social workers. The consequences are an impaired quality of life and a great deal of expense in the welfare system. Since 1996, a specialized structured treatment and teaching program for patients with type-2 diabetes mellitus, insulin therapy, and impaired cognitive function (DikoL) has been developed. Main differences in comparison to established programs were less theoretical topics (no pathophysiology, no insulin action, no complicated calculation of carbohydrate pounds) and more time for practical exercise. In a randomized prospective study, the effectiveness of the DikoL program was evaluated. PATIENTS AND METHODS: All patients with type-2 diabetes mellitus (n = 106, age 68.6 +/- 8.7 years, median diabetes duration 10.3 [0.03-35.4] years, HbAlC 10.3+ 1.7% [HPLC, Diamat, normal range 4.5-6.3%], cognitive function 87.7 +12.3 IQ points), admitted to hospital to participate in a structured treatment and teaching program between April 1999 and June 2000, were studied. Patients with impaired cognitive function (< 91 IQ points) were randomized: they participated either in an established structured treatment and teaching program according to Berger et al. (standard group: n = 35) or in the DikoL program(DikoL group: n = 33). Immediately after participation and 0.5 years later, the quality of diabetes control, patients' knowledge of diabetes, their ability for diabetes self-management, and their satisfaction with the program were evaluated. RESULTS: Patients of the DikoL group had a comparable quality of diabetes control (HbAlc: DikoL vs. standard group: 8.5 + 1.3 vs. 8.3 +/- 1.4%; p = 0.62)and diabetes-related knowledge (DikoL vs. standard group: 9.6 +/- 4.4 vs.10.3 + 3.8 points; p = 0.52), but significantly better results in respect of their ability for diabetes self-management (DikoL vs. standard group: 15.9 +/- 3.1 vs. 12.5 +/- 4.1 points; p = 0.001) than patients of the standard group. Moreover, in the DikoL group there was a tendency to a lower number of patients needing third-party assistance (n = 1 patient of the DikoL group vs. n = 5 patients of the standard group; p = 0.13). There were no acute complications (hypoglycemia, comata, and foot ulcers) in neither group. Following participation in the DikoL program, patients reached a better score in the questionnaire evaluating satisfaction with the treatment and teaching program (DikoL vs. standard group:52.5 + 4.5 vs. 44.7 + 76 points; p < 0,001). CONCLUSION: Following the wishes of the majority of diabetes educators as well as diabetologists but also patients' wishes, a specially designed structured treatment and teaching program for patients with type-2 diabetes mellitus, insulin therapy, and impaired cognitive function was designed. DikoL is the first program evaluated in a randomized, prospective trial. It clearly demonstrated a bet-ter outcome for patients with impaired cognitive function in respect of diabetes self-management and satisfaction. With its implementation, patients' quality of diabetes care can be improved in a substantial manner.

Aged↗
PubMed2004

Identification of the receptor for advanced glycation end products in synovial tissue of patients with rheumatoid arthritis.

OBJECTIVES: Generation of advanced glycation end products (AGE) is an inevitable process in vivo and can be accelerated under pathologic conditions such as oxidative stress, e.g. in rheumatoid arthritis (RA). This process is mediated by the AGE-specific receptor (RAGE). In this study we analysed the presence of RAGE in RA and osteoarthritic (OA) synovial tissue using immunohistology. METHODS: Frozen synovial tissue samples from 11 RA patients and 12 OA patients were treated with goat anti-RAGE immunoglobulin G (IgG) and rabbit antigoat IgG. Immunostaining was visualised with streptavidin horse radish peroxidase (chromogen amino-ethyl-carbazole). Cell differentiation was performed with antibodies against CD68, CD45RO, and CD20. RESULTS: In 9/11 RA and 8/12 OA synovial specimens, RAGE was detected in synovial lining, sublining, and stroma. In RA, many T cells (CD45RO(+)) and some macrophages (CD68(+)) showed positive immunostaining for RAGE, whereas B cells were mostly negative. We found no difference in staining patterns between the RA and OA samples. CONCLUSIONS: We detected RAGE in RA and OA synovial tissue. The presence of RAGE on macrophages, T cells, and some B cells suggests its role in the pathogenesis of inflammatory joint disease.

Aged↗
PubMed2004

Characterization of the postglomerular renal metabolism of lepirudin in healthy volunteers.

INTRODUCTION: The anticoagulant r-hirudin lepirudin is eliminated exclusively via the kidneys. We examined the C-terminal amino acid degradation of lepirudin by the proximal kidney tubulus cells in humans as well as the antithrombotic efficacy of the metabolites and quantified the metabolite portions. MATERIALS AND METHODS: In vitro metabolites of lepirudin were produced by adding 250 microg lepirudin to urine of three healthy volunteers and a concentration of 100 ml fresh urine to 1.5 ml and subsequent separation by high performance liquid chromatography. Anticoagulant activities of the mass spectrometrically identified metabolites were measured by ecarin clotting time and protein determination with bicinchoninic acid. In 10 healthy volunteers 1 mg lepirudin was administered intravenously, urine was collected during the following 2 h. The urine amount containing 50 microg lepirudin measured by ecarin clotting time was enzyme-inactivated and measured analogously to the in vitro samples. RESULTS: The in vitro generated metabolites were shortened amino acid by amino acid at the C-terminal end, up to five amino acids. Their anticoagulant activity was reduced to 92.6% (M64), 80.1% (M63) and 74.4% (M60,61,62) in comparison to lepirudin. Lepirudin (57.9 +/- 8.6%) was eliminated unchanged via the kidneys. Identical to the in vitro situation metabolite fragments were built in the distribution M64 = 8.1 +/- 5.7%, M63 = 21.1 +/- 6.5%, and M60,61,62 = 12.9 +/- 4.5%. CONCLUSIONS: Lepirudin is metabolized spontaneously in more than 10-fold concentrated urine. Metabolization of lepirudin takes place in the proximal tubulus cells as well. In vitro, the degradation takes place amino acid by amino acid, but in vivo even dipeptides and perhaps tripeptides are degraded.

Adult↗
PubMed2004

Anticoagulant efficacy of PEG-Hirudin in patients on maintenance hemodialysis.

BACKGROUND: Heparins are currently the anticoagulants of choice in long-term hemodialysis (HD). Because of their shortcomings, including the increasing incidence of heparin-induced thrombocytopenia (HIT II), alternative anticoagulation is necessary. The study objectives were to provide safe and effective HD by investigating an appropriate PEG (polyethylene glycol)-Hirudin dosage regimen in patients on HD, as well as to compare the safety, tolerability, and efficacy of PEG-Hirudin with that of unfractionated heparin (UFH). METHODS: Twenty patients (12 males, 8 females, mean age 57.8 years) with end-stage renal disease (ESRD) took part in the study. Dialysis sessions lasting a mean of 4.3 hours (QB 250 to 300 mL/min, QD 500 mL/min) were performed 3 times a week with a Gambro GFS plus 16 dialyzer. Ten patients (group I) received UFH at 3 regular dialysis sessions (HD1-3) followed by 5 dialysis sessions using PEG-Hirudin (HD4-8). Another 10 patients (group II) received UFH at 3 regular dialysis sessions (HD1-3) followed by 10 sessions on PEG-Hirudin (HD4-13). The starting dose of PEG-Hirudin was a single bolus injection of 80 microg/kg BW (HD4), except for the first patient, who received 50 microg/kg BW followed by a 12 microg/kg bolus. Before each of the following sessions (HD5-13), an individualized PEG-Hirudin dose of between 26 to 65 microg/kg body weight (BW) (mean dose 41 microg/kg BW) was injected. PEG-Hirudin plasma and blood concentrations derived from anti-Iia activity and ecarin clotting time (ECT), respectively, activated partial thromboplastin time (aPTT), bleeding time, and arteriovenous (AV) fistula compression time were investigated to calculate the pharmacokinetic parameters or to assess anticoagulant efficacy. RESULTS: Mean predialysis PEG-Hirudin plasma concentrations increased up to a maximum of 488 ng/mL in group I (HD8) and up to 536 ng/mL in group II (HD8). Mean plasma concentrations measured at 5 minutes after the 1st (HD4), 5th (HD8), and 10th (HD13) PEG-Hirudin injection ranged from 1076 to 1298 ng/mL. Mean post-dialysis plasma levels ranged from 818 to 995 ng/mL. Mean predialysis aPTT was not affected by UFH, but was prolonged by 46 to 56 seconds by PEG-Hirudin. Five minutes after injecting PEG-Hirudin or UFH, mean aPTT was prolonged to a maximum of 85 and 188 seconds, respectively. Mean post-dialysis aPTT values ranged from 60 to 68 seconds after PEG-Hirudin and 34 to 46 seconds after UFH. PEG-Hirudin was well tolerated; no serious adverse events or bleeding complications were observed. Safety assessments yielded no significant difference between the two anticoagulants. CONCLUSION: This pilot study confirmed the usefulness and tolerability of a PEG-Hirudin dose regimen consisting of a single, fixed bolus dose of 80 microg/kg BW injected before starting the first dialysis session (HD4) and followed by a dose titration period over at least 4 sessions (HD5-8), which again was followed by a fixed maintenance dose period (HD9-13). On the basis of PEG-Hirudin data from patients with various degrees of renal insufficiency but not undergoing hemodialysis and prior recombinant-hirudin (r-hirudin) experience, patients were titrated into an EC-controlled dose range that proved to be efficacious enough to prevent clotting and safe enough to prevent bleeding. Due to the favorable pharmacokinetic properties of PEG-Hirudin, a residual anticoagulant effect is maintained in the intervals between dialysis sessions, and this permanent state of anticoagulation may prevent vascular access complications as well as other vascular events.

Adult↗
PubMed2004

Potential cardiovascular risk factors in chronic kidney disease: AGEs, total homocysteine and metabolites, and the C-reactive protein.

BACKGROUND: Total homocysteine (tHcy) and advanced glycation end-products (AGEs) are implicated in the pathogenesis of vascular damage. This study aimed to investigate whether elevated serum levels of the AGEs pentosidine, N(epsilon)-carboxymethyllysine (CML) and imidazolone; tHcy, cystathionine, methylmalonic acid (MMA), and 2-methylcitric acid (2-MCA), as well as C-reactive protein (CRP), are related to a higher risk for cardiovascular events. METHODS: A total of 232 patients with chronic kidney diseases (mean age 57.6 +/- 13.1 years, 82 female and 150 male); 99 with chronic renal failure (CRF), 84 maintenance hemodialysis patients and 49 renal transplant recipients were followed for 2 years. The relationship between the parameters of interest, conventional risk factors and elevated levels of CRP with cardiovascular events was tested in all subjects by the Cox proportional hazards model. RESULTS: Mean serum levels of AGEs, tHcy, and of the metabolites were found to be significantly increased in all three groups compared to the healthy subjects (P < 0.01, respectively). Fifty-three cardiovascular events occurred during follow-up; a total of 40 patients died. Final multivariate analysis showed diabetes (RR 2.06, 95% CI 1.17-3.60, P= 0.013), end-stage renal disease (ESRD) (RR 4.88, 95% CI 2.40-9.89, P < 0.001) and elevated CRP levels (RR 2.00, 95% CI 1.11-3.60, P= 0.021) as independent risk factors for cardiovascular events. CONCLUSION: Data from a group consisting of patients with CRF, patients undergoing maintenance hemodialysis treatment, and renal transplant recipients provide evidence that conventional risk factors such as the presence of diabetes, ESRD, as well as elevated levels of the considered risk factor CRP, seem to play a more important role for cardiovascular outcome in patients with chronic kidney disease than elevated levels of AGEs, tHcy, and related metabolites. The evidence suggests that routine CRP measurement can be recommended in cases of chronic renal insufficiency.

Aged↗
PubMed2003

[Nephrology-part 3: Urinary tract infections].

Urinary tract infections are one of the most common bacterial infectious diseases in humans. Depending on the localization and the effectiveness of pathogenetic factors, various clinical pictures (lower urinary tract infection, pyelonephritis, asymptomatic bacteriuria) have to be differentiated. There are virulence factors of microorganisms on the one hand and defense mechanisms on the other, which influence the manifestation and the course of disease. The process of bacterial attachment to the epithelial cells of the boundary layer, the internalization and invasion of bacteria could be important for acute and chronic disease. Disturbances of local defense mechanisms, such as increased urinary glucose concentration in diabetes or variations of Tamm-Horsfall protein and defensin levels, may influence the course of infection. On the basis of microbiological and laboratory findings as well as the results of clinical and ultrasound procedures, the decision on the therapeutic strategy should be made. There are different treatment recommendations for acute uncomplicated and complicated cases as well as for chronic diseases. Future investigations should focus on effective therapeutic options for special immunocompromised patients in relation to the microbiological aspects and defense mechanisms of the host.

Anti-Bacterial Agents↗
PubMed2003

Orbital inflammatory pseudotumor due to hypersensitivity vasculitis and mononeuritis multiplex in a patient with atypical, cANCA-positive Wegener's granulomatosis.

OBJECTIVE: We report on a 60-year-old woman with a retro-orbital pseudotumor and polyneuropathy. The retro-orbital inflammation was histologically diagnosed as hypersensitivity vasculitis (HV). As cytoplasmatic antineutrophilic cytoplasmatic antibody (cANCA) and anti-proteinase-3 antibody were detected, the differential diagnosis also included atypical Wegener's granulomatosis. Hypersensitivity vasculitis is defined as small-vessel vasculitis mediated by the deposition of immune complexes (Arthus reaction) after exposure to various agents such as drugs, toxins, and infections. Since an inflammatory retro-orbital pseudotumor due to HV has not previously been reported, the following case is presented. METHODS AND MAIN OUTCOME MEASURES: Magnetic resonance imaging (MRI) revealed retro-orbital infiltrate without granuloma. Histology from an orbital biopsy confirmed HV. Electromyography was used for the diagnosis of polyneuropathy. Serum investigation indicated erythrocyte sedimentation rate (ESR) >100 mm/h, C-reactive protein (CRP) 223 mg/l, antinuclear antibodies 1:80, and cANCA 100 U/ml. RESULTS: The bilateral orbital pseudotumor, polyneuropathy, and serum levels of inflammation reactants (ESR and CRP) improved from therapy with corticosteroids (1 g of methylprednisolone initially) and azathioprine (150 mg/day). CONCLUSIONS: Because of cANCA and anti-proteinase-3 antibody positivity, this case can be viewed more as an atypical Wegener's granulomatosis than a systemic HV. The causal variety of inflammatory orbital pseudotumor, including HV and different therapeutic consequences, requires histological differentiation from usual orbital pseudotumors.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2003

[Nephrology--Part 2. Strategies in the immunosuppression after kidney transplantation].

BACKGROUND: As a result of better prevention and treatment of acute rejection, 1-year kidney graft survival exceeds 90% in most centers. By contrast, the rate of attrition over the long-term did not change during the last decades. As current immunosuppressive agents lack specificity (infection, malignant disease), the search for the ideal immunosuppressive agent or drug combinations continues. The goal is to prevent chronic allograft nephropathy, toxicity, infections, malignancies, and metabolic problems. Long-term immunosuppression should be reliable and stable. PURPOSE: This article is aiming to discuss current strategies such as nephrotoxicity-free therapy, avoidance or withdrawal of steroids, therapy of acute rejection, and immunosuppressive therapy in high-risk patients.

Chronic Disease↗