Serum Uromodulin in Children and Adolescents with Type 1 Diabetes Mellitus and Controls: Its Potential Role in Kidney Health.

INTRODUCTION: Uromodulin is a kidney-specific tubular protein, and its assessment in serum (sUMOD) reveals the potential as a novel marker for function and the integrity of renal parenchymal cells and does not directly depend on the glomerular filtration rate. Early diabetic nephropathy parallels glomerular hyperfiltration, often leading to diagnostic misinterpretation. Moreover, traditional kidney function markers are not able to diagnose structural lesions. Recent data show that sUMOD is linked to glucose intolerance in adults. Thus, we launched to assess the hypothesis that sUMOD is also associated with kidney function, biometric data, and quality of metabolic control in children/adolescents with type 1 diabetes. PATIENTS AND METHODS: Patients with type 1 diabetes (n=135) and healthy controls (n=69) were recruited to participate in the trial. Clinical, biometrical data, sUMOD, and other laboratory parameters were assessed. RESULTS: The mean concentrations of sUMOD in diabetic patients and controls were comparable (201.19±103.22 vs. 198.32±84.27 ng/mL, p=0.832). However, in contrast to healthy controls, sUMOD levels in patients with diabetes were associated with serum-creatinine (r=-0.368, p<0.0001), age (r=-0.350, p<0.0001), height (r=-0.379, p<0.0001), body weight (r=-0.394, p<0.0001), Body mass index (r=-0.292, p=0.001), daily insulin dosage (r=-0.300, p<0.0001), HbA1c (%) (r=-0.190, p=0.027), standardized HbA1c/IFCC (mmol/mol) (r=-0.189, p=0.028), and systolic (r=-0.299, p<0.0001) and diastolic (r=-0.235, p=0.006) arterial blood pressure. CONCLUSIONS: Our study shows that children/adolescents with type 1 diabetes disclose similar sUMOD concentrations as healthy controls. Serum UMOD appears to indicate higher risks for kidney tissue remodeling and possibly subsequent cardiovascular alterations. However, further studies are mandatory to settle these findings.

[Quality of Blood Pressure Control in General Practice Using Ambulatory Blood Pressure Monitoring - a Retrospective Monocentric Cross-Sectional Study]. / Qualität der Blutdruckeinstellung in der hausärztlichen Praxis unter Verwendung der 24-Stunden-Langzeitblutdruckmessung ­ eine retrospektive monozentrische Querschnittsstudie.

INTRODUCTION: The diagnosis and therapy of arterial hypertension is a continuous challenge in general practice. The aim of this study is to analyze the nature and effectiveness of blood pressure control in patients with known arterial hypertension in a primary care practice using office- (OBPM) and ambulatory (ABPM) blood pressure measurement. METHODS: 283 patients (90 % of all regularly treated patients having hypertension) were retrospectively examined for the achievement of the target blood pressure values in ABPM and OBPM in the past 1 to 2 years. Target blood pressure levels were in line with current ESH recommendations (office blood pressure < 140/90 mmHg, mean 24-h ABPM < 130/80 mmHg). RESULTS: The OBPM of all patients (age: 68 ±â€Š12.7, 48 % women) was 132 ±â€Š11.8/80 ±â€Š4.2 mmHg, the 24-h ABPM was 128 ±â€Š10.7/74 ±â€Š7.9 mmHg. An isolated office hypertension had 11.3 %, a masked hypertension 21.9 %. Only 33.9 % had physiological dipping behavior (49.1 % non-dipper, 13.8 % reverse dipper and 3.2 % extreme dipper). The blood pressure control rate (reaching the target blood pressure) was 67.8 % in the OBPM and 57.2 % in the 24-h ABPM. 23.0 % were treated with monotherapy, 37.5 % with dual combination, 19.8 % with a triple combination and 14.5 % with > 3 antihypertensives. 83.9 % of all had RAS blockers. The OBPM target was achieved in 75.0 % under a triple and 71.7 % under dual combination. The 24-hour ABPM target was mostly achieved in patients requiring only monotherapy (66.2 %) or dual therapy (60.4 %); others < 60 %. CONCLUSION: In the family practice examined, the treatment control of patients with arterial hypertension was mostly guideline-based and better than described in the literature. The parallel and consistent implementation of ABPM in addition to OBPM as well as the high prescription rate of RAS blockers and recommended combination therapies might be the key for this result.

Predictors and determinants for weight reduction in overweight and obese children and adolescents.

INTRODUCTION: Worldwide, overweight and obesity are known as posing serious health risks. Successful methods for weight reduction have remained elusive. This multicenter non-randomised trial aimed to identify parameters and determinants of long-term weight reduction. PATIENTS AND METHODS: A total of 143/159 overweight and obese children and adolescents (90 %) completed the prospective multicenter trial (age 13.9±2.4 years, BMI 31.2±5.4kg/m2, BMI-SDS 2.51±0.57). During a 6-week rehabilitation period the patients participated in a structured treatment and teaching program (STTP). Following in-patient treatment the children and adolescents were monitored over a period of 24 months (physical examination, measurements of BMI, BMI-SDS, body composition, carotid intima-media thickness, laboratory parameters, blood pressure, standardized questionnaires to assess socio-demographic and socio-economic parameters, eating behavior, well-being, quality of life, intelligence, intrafamilial conflicts, self-efficacy, resilience, sense of coherence, stress management, social support, actual body shape). RESULTS: 66% of the children and adolescents had abnormal laboratory parameters as well as higher blood pressure and/or an increased carotid intima-media thickness. The mean carotid intima-media thickness was 0.53±0.09mm (range 0.40 to 0.80); 15% of the patients showed normal range values (< 0.45mm), 40% a slightly elevated (≥ 0.45 to ≤ 0.50mm) and 45% an elevated (> 0.50mm) thickness. After the inpatient treatment lasting 40.4±4.1 (range 28 to 49) days, children and adolescents reached a mean weight reduction of 5.52±3.94 (0.4 to 13.3) kg (p<0.01) that was accompanied by a reduction in body fat mass. Using multivariate analyses, the most important psychological factors associated with long-term weight reduction were identified (R-square=0.53): well-being (ß=-0.543), resilience (ß=0.434), and sense of coherence (ß=0.315). CONCLUSION: The different parameters (i. e., well-being, resilience, sense of coherence) have demonstrated their utility, and strategies should be developed allowing an adaption of these into the STTPs.

Identification of Predictors for Weight Reduction in Children and Adolescents with Overweight and Obesity (IDA-Insel Survey).

INTRODUCTION: Worldwide, overweight and obesity are known as posing serious health risks. Successful methods of prevention and therapy for overweight and obesity have remained elusive. It was the aim of the present trial to identify parameters and determinants to guarantee long-term weight reduction. PATIENTS AND METHODS: In total 143/159 children and adolescents (90%) with overweight and obesity completed the prospective, multicenter trial (age 13.9 ± 2.4 years, BMI 31.2 ± 5.4 kg/m², BMI-SDS 2.51 ± 0.57). During a six-week rehabilitation patients participated in a structured treatment and teaching program (STTP). Following the inpatient treatment the children and adolescents were monitored over a period of 24 months (physical examination, measurements of BMI, BMI-SDS, body composition, carotid intima-media thickness, laboratory parameters, blood pressure, and standardized questionnaires to assess socio-demographic, socio-economic parameters, eating behavior, well-being, quality of life, intelligence, intrafamilial conflicts, self-efficacy, resilience, sense of coherence, stress-management, social support, and actual body shape). RESULTS: 66% of the children and adolescents showed non-normal laboratory parameters as well as higher blood pressure and/or an increased carotid intima-media thickness. Mean thickness of carotid intima-media was 0.53 ± 0.09 mm (range, 0.40-0.80); 15% of the patients showed a normal range (<0.45 mm), 40% slightly elevated (0.45-0.50 mm) and 45% an elevated (>0.50 mm) thickness. After an inpatient treatment lasting 40.4 ± 4.1 (range, 28-49) days, children and adolescents reached a mean weight reduction of 5.52 ± 3.94 (0.4-13.3) kg (p < 0.01) accompanied by a reduction of body fat mass. Performing multivariate analyses, the most important psychological factors associated with long-term weight reduction were identified (R-square = 0.53): Well-being (ß = -0.543), resilience (ß = 0.434) and intrafamilial conflicts (ß = 0.315). CONCLUSION: The different parameters (i.e., resilience, intrafamilial conflicts, structured daily schedule) have demonstrated their utility and strategies should be developed allowing an adaption of these into the STTPs and the integration of intervention into the therapeutic setting.

Plasma copeptin in children and adolescents with type 1 diabetes mellitus in comparison to healthy controls.

UNLABELLED: In a cohort of children and adolescents with type 1 diabetes mellitus the trial tested the hypothesis that copeptin levels are associated with kidney function, biometrical data and quality of diabetes control. PATIENTS AND METHODS: A total of 141 subjects were recruited to participate in the trial: 80 patients with type 1 diabetes (13.0±3.4years, HbA1c 7.85±1.42%) and 61 healthy controls (12.4±2.8years). Clinical and socio-economic data were assessed. A sandwich immunoassay (B.R.A.H.M.S. GmbH/Thermo Fisher Scientific, Hennigsdorf/Berlin, Germany) was used for measuring plasma copeptin levels. RESULTS: The mean concentration of copeptin in the diabetic patients was 4.75±3.46pmol/l. There was a strong inverse correlation between copeptin and GFR (r=-0.86, p=0.021), as well as with total cholesterol (r=-0.23, p=0.041), LDL-cholesterol (r=-0.24, p=0.036), but not with serum creatinine, albuminuria, HbA1c, blood glucose, MAGE, CRP, systolic or diastolic blood pressure or age, diabetes duration, weight, height and BMI. Comparing patients with a diabetes duration of ⩾7years (n=45) with those with a diabetes duration <7years (n=35), patients with a longer duration of diabetes had higher copeptin levels (5.24±2.26 vs 4.13±2.86, p=0.045). Performing multivariate analyses only GFR could be identified as a parameter associated with copeptin (R-square=0.05, ß=-0.23, p=0.032). In the healthy controls mean copeptin concentration was 5.56±3.15pmol/l. The copeptin concentration and GFR were inversely correlated as well (r=-0.61, p=0.034). However, other correlation and multivariate analyses revealed no further significant results. Comparing patients with type 1 diabetes mellitus with the healthy controls, the diabetes patients revealed no significant difference with respect to copeptin (p=0.24), serum creatinine (49.8±11.9 vs 50.4±11.0µmol/l, p=0.53) or GFR (102.4±23.3 vs 104.5±19.1ml/min, p=0.47). On the other hand, patients with type 1 diabetes had lower concentrations of CRP (1.66±3.91 vs 3.21±3.04µg/ml, p=0,013), triglycerides (0.88±0.53 vs 1.13±0.60mmol/l, p=0.010), and a lower ratio of LDL-/HLD-cholesterol (1.73±0.69 vs 2.32±0.80, p<0.001), as well as lower body weight (51.3±18.0 vs 60.3±15.7kg, p=0.002) and BMI (19.7±3.8 vs 23.2±2.9kg/m(2), p<0.001). In contrast to the controls, the diabetes patients had higher blood glucose levels at the time of examination (8.2±3.8 vs 4.7±0.5mmol/l, p<0.001), higher HDL-cholesterol levels (1.59±0.34 vs 1.26±0.24mmol/l, p<0.001), as well as higher education and higher educational levels of the mothers. CONCLUSIONS: The present trial revealed a clear association between GFR and copeptin in children and adolescents with type 1 diabetes mellitus. Hence, copeptin can be considered as a marker of renal function.

Advanced glycation end products and ß(2)-microglobulin as predictors of carpal tunnel syndrome in hemodialysis patients.

BACKGROUND/AIMS: Carpal tunnel syndrome (CTS) is a common clinical presentation of dialysis-related amyloidosis. It was determined whether ß(2)-microglobulin (ß2M) and advanced glycation end products in serum are predictors of CTS in dialysis patients. METHODS: A total of 385 hemodialysis patients were screened for CTS. ß2M in serum was determined by a competitive enzyme-linked immunoassay, CML by a competitive enzyme-linked immunosorbent assay and total pentosidine by reverse-phase high-performance liquid chromatography. RESULTS: 127 patients (33%) were treated with biocompatible membranes, 174 (45%) with high-flux dialysis. 122 patients (31.7%) had clinical signs of CTS. Significant predictors of CTS were: age, female gender, serum ß2M, total protein, dialysis with non-biocompatible high-flux dialysis compared to non-biocompatible low-flux dialysis, Kt/V and serum concentration of CML (OR 2.47 for the 3rd vs. 1st quartile, 95% CI 1.229-4.961, p = 0.011). CONCLUSION: The prevalence of CTS as a possible manifestation of dialysis-related amyloidosis is still high. Serum concentration of CML may be a predictor of CTS besides ß2M and malnutrition.

Vitamin B6 metabolism in chronic kidney disease--relation to transsulfuration, advanced glycation and cardiovascular disease.

BACKGROUND: Vitamin deficiency is common in chronic kidney disease (CKD). Data on B(6) supply and possible relationships to cardiovascular events (CVE) in CKD are rare. Pyridoxamine exerts inhibitory effects on the formation of advanced glycation endproducts (AGE) implicated in the pathogenesis of CKD and atherosclerosis. METHODS: In 48 CKD patients at stage 2-4, 72 hemodialysis patients (HD), 38 renal transplant recipients (RTR) and 141 healthy controls (mean age 58 +/- 13, 61 +/- 12, 50 +/- 12 and 54 +/- 16 years, respectively), plasma and red blood cell (RBC) concentrations of pyridoxal-5'-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (PA), pyridoxamine-5'-phosphate (PMP) and of the AGE pentosidine were measured by high-performance liquid chromatography, N(epsilon)-(carboxymethyl)lysine and imidazolone by an ELISA, and total homocysteine and cystathionine by gas chromatography-mass spectrometry. RESULTS: Despite routine low-dose vitamin supplementation in HD, plasma PLP was decreased in HD (79 +/- 69 nmol/l) compared with CKD stage 2-4 patients (497 +/- 944 nmol/l), RTR (416 +/- 604 nmol/l) and controls (159 +/- 230 nmol/l; p < 0.001). Plasma PA was significantly increased in HD (11,667 +/- 17,871 nmol/l) in comparison with CKD stage 2-4 (435 +/- 441 nmol/l), RTR (583 +/- 668 nmol/l) and controls (46 +/- 49 nmol/l; p < 0.001). B(6) forms were significantly affected by renal function (R = 0.792, p < 0.001 for CKD stage 2-4). There was no relation of vitamers with a history of CVE. Relationships between B(6) forms and AGE (RBC-PMP with pentosidine in CKD stage 2-4: R = -0.351, p < 0.05) were found. CONCLUSION: HD patients showed a deficiency in PLP in plasma but not in RBC. Prospective trials are needed to elucidate the potential role of elevated PA on cardiovascular and renal outcome in CKD. Vitamin B(6) supplementation might be successful in preventing AGE-related pathologies.

Retinal vessel response to flicker light in children and adolescents with type 1 diabetes mellitus and overweight or obesity.

UNLABELLED: It was the goal of the trial to assess cardiovascular risk factors in children and adolescents with type 1 diabetes mellitus or overweight/obesity. All children and adolescents (n=77 [n=45 patients with diabetes mellitus, n=32 patients with overweight/obesity]) admitted to our hospital during the period from 01/07 to 31/08/2006 were included in the trial. Socio-demographic and laboratory data (age, sex, diabetes duration, BMI, BMI-SDS, HbA1c, fasting blood glucose, oGTT in patients with overweight/obesity, lipids, CRP, TSH, creatinine, and microalbuminuria) were assessed. The diameter of a retinal arterial and a venous segment was measured continuously on-line with a Dynamic Vessel Analyzer, carotid intima-media thickness (IMT) was measured, and 24-h-blood pressure monitoring was applied. RESULTS: Flicker light stimulation induces a comparable arterial dilatation in patients with type 1 diabetes and overweight/obesity. Univariate ANOVA in patients with type 1 diabetes shows an influence of diastolic blood pressure on arterial dilatation. Other factors such as BMI, age, diabetes duration, smoking, sex, HbA1c and insulin dose/kg had no effect. CONCLUSIONS: In children and adolescents with diabetes or overweight/obesity retinal vascular alterations seem to be more sensitive and already present before the occurrence of classic cardiovascular markers.

Serum levels of the advanced glycation end products Nepsilon-carboxymethyllysine and pentosidine are not influenced by treatment with the angiotensin receptor II type 1 blocker irbesartan in patients with type 2 diabetic nephropathy and hypertension.

BACKGROUND/AIMS: The aim of this post-hoc analysis of a prospective study in patients with type 2 diabetic nephropathy was to investigate whether treatment with the angiotensin II type 1 receptor blocker irbesartan leads to a reduction in the serum levels of the advanced glycation end products (AGEs) pentosidine and N(epsilon)-carboxymethyllysine (CML). METHODS: One hundred and ninety-six patients of the Irbesartan in Diabetic Nephropathy Trial cohort (mean age 61 +/- 6.5 years, 62 female, 134 male) with a mean estimated glomerular filtration rate of 47.7 ml/min were treated with irbesartan (n = 65), the calcium channel blocker amlodipine (n = 61) or by placebo (n = 70). Serum levels of pentosidine and CML were measured at baseline and after follow-up (23.4 months). RESULTS: Estimated glomerular filtration rate decreased in all groups by a mean of 8.6 ml/min. Serum levels of AGEs increased significantly (p < 0.001) during follow-up. After controlling for renal function and total protein concentration, changes were 53, 55, 50% for pentosidine and 29, 24, 23% for CML (irbesartan, amlodipine and placebo group, respectively). The increase was not significantly different between the treatment groups. CONCLUSION: Irbesartan did not alter the increase in pentosidine and CML in serum of type 2 diabetic patients with progressive nephropathy. This finding suggests that angiotensin receptor blockade alone is insufficient to reduce serum levels of AGEs in diabetic nephropathy.

Long-term treatment of obese children and adolescents using a telemedicine support programme.

A total of 140 obese patients (mean age 14 years) participated in a structured treatment and teaching programme (STTP) in hospital, with the aim of weight reduction. At both the start and finish of the STTP, patients underwent clinical and psychological examination. During an average hospital stay of 35 days, their mean bodyweight decreased from 82.4 kg to 76.0 kg (P < 0.001). Patients were then followed up with a telemedicine support programme. During the next 12 months, the acceptance of the telemedicine support programme declined from 93% to 46%. The body mass index was 30.5 kg/m(2) at admission and 27.7 kg/m(2) at 12-month follow-up (P < 0.05). In parallel, wellbeing and treatment satisfaction increased, and there was a positive effect on eating behaviour and exercise. Intervention was needed in up to 64% of the children and adolescents who participated in the programme, most frequently due to poor results in exercise. Telemedical follow-up care and counselling seemed to be highly effective, and allowed not only an initial weight reduction, but long-term stabilization as well.

Increased binding of beta-2-microglobulin to blood cells in dialysis patients treated with high-flux dialyzers compared with low-flux membranes contributed to reduced beta-2-microglobulin concentrations. Results of a cross-over study.

BACKGROUND: Patients on long-term dialysis eventually develop amyloid deposits with beta2-microglobulin as a predominant component. Although several studies have suggested that high-flux membranes reduce beta2-microglobulin in plasma compared with low-flux dialyzers, the mechanisms underlying this observation are still discussed. METHODS: We revisited this important subject and measured beta2-microglobulin in the plasma of healthy individuals (n = 8), and patients undergoing hemodialysis (n = 20) who for assigned periods of time were either treated with a low-flux membrane (cuprophan) or high-flux (polyamide) dialyzer with an ELISA. The number of blood cells was determined by FACS. Beta2-microglobulin was also measured on the surface of granulocytes, lymphocytes, and monocytes before, directly after, and 4 h after hemodialysis. Expression of beta2-microglobulin, c-fos, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 mRNA was determined in whole blood samples with quantitative RT-PCR using an internal standard in parallel. In the second part of the study, patients were assigned in a two-group cross-over design either to low- or high-flux dialyzers (n = 9 in each group), and dialyzer membranes were changed every 4 weeks for two consecutive periods. Serum beta2-microglobulin concentrations were measured at the end of each period. RESULTS: Healthy controls had a low plasma beta2-microglobulin level of 1.2 +/- 0.3 mg/l. Before hemodialysis, patients on low-flux dialyzers had a plasma beta2-microglobulin level of 42.0 +/- 14.0 mg/l, patients treated with high-flux dialyzers 21.5 +/- 10.8 mg/l (p < 0.05 vs. low-flux dialyzers). In contrast, there was no significant difference in plasma concentrations of active transforming growth factor-beta1 with the two different membrane types. The difference in serum beta2-microglobulin between low- and high-flux membranes was more prominent directly after hemodialysis as well as 4 h after hemodialysis compared with the values directly before the start of treatment. At all studied time-points, leukocytes and platelets were significantly higher in patients on low-flux membranes. Healthy control persons exhibited a significantly higher amount of beta2-microglobulin bound to granulocytes, lymphocytes, and monocytes compared with dialysis patients. Interestingly, beta2-microglobulin bound to granulocytes, lymphocytes, and monocytes was significantly increased in patients treated with high-flux membranes compared with low-flux filters. Quantitative RT-PCR revealed no significant difference in beta2-microglobulin expression in whole blood before hemodialysis, directly after hemodialysis, and 4 h after hemodialysis. However, TNF-alpha and c-fos transcripts were significantly higher in whole blood obtained from patients treated with low-flux membranes compared to high-flux dialyzers. The two-group cross-over study over three periods of 4 weeks revealed that switching from low-flux to high-flux dialyzers significantly reduced serum beta2-microglobulin levels. CONCLUSION: Patients treated with a polyamide high-flux membrane had lower beta2-microglobulin concentrations compared with those patients on low-flux dialyzers. This difference might not be mediated by an increase in beta2-microglobulin mRNA, but may be caused by less beta2-microglobulin released from the blood cells in patients treated with high-flux dialyzers, in addition to a better beta2-microglobulin clearance.

Analysis of glycoproteins in human serum by means of glycospecific magnetic bead separation and LC-MALDI-TOF/TOF analysis with automated glycopeptide detection.

Comprehensive proteomic analyses require efficient and selective pre-fractionation to facilitate analysis of post-translationally modified peptides and proteins, and automated analysis workflows enabling the detection, identification, and structural characterization of the corresponding peptide modifications. Human serum contains a high number of glycoproteins, comprising several orders of magnitude in concentration. Thereby, isolation and subsequent identification of low-abundant glycoproteins from serum is a challenging task. selective capturing of glycopeptides and -proteins was attained by means of magnetic particles specifically functionalized with lectins or boronic acids that bind to various structural motifs. Human serum was incubated with differentially functionalized magnetic micro-particles (lectins or boronic acids), and isolated proteins were digested with trypsin. Subsequently, the resulting complex mixture of peptides and glycopeptides was subjected to LC-MALDI analysis and database searching. In parallel, a second magnetic bead capturing was performed on the peptide level to separate and analyze by LC-MALDI intact glycopeptides, both peptide sequence and glycan structure. Detection of glycopeptides was achieved by means of a software algorithm that allows extraction and characterization of potential glycopeptide candidates from large LC-MALDI-MS/MS data sets, based on N-glycopeptide-specific fragmentation patterns and characteristic fragment mass peaks, respectively. By means of fast and simple glycospecific capturing applied in conjunction with extensive LC-MALDI-MS/MS analysis and novel data analysis tools, a high number of low-abundant proteins were identified, comprising known or predicted glycosylation sites. According to the specific binding preferences of the different types of beads, complementary results were obtained from the experiments using either magnetic ConA-, LCA-, WGA-, and boronic acid beads, respectively.

Trends in the management of arterial hypertension in patients with type 1 and insulin-treated type 2 diabetes mellitus over a period of 10 years (1989/1990-1994/1995). Results of the JEVIN trial.

UNLABELLED: For populations of patients with insulin-treated diabetes mellitus, information about the quality of blood pressure control, an independent risk factor for cardiovascular mortality and morbidity, is widely lacking. Hence, it was the goal of the trial to evaluate the prevalence of arterial hypertension, the quality of blood pressure control and changes in treatment modalities over a period of 10 years. PATIENTS AND METHODS: In 1989/1990, Jena's St. Vincent (JEVIN) Trial started as a prospective, population-based survey with 10-year follow-up of all patients with type 1 and insulin-treated type 2 diabetes mellitus aged 16 to 60 years and living in the city of Jena, Thuringia, Germany. RESULTS: In 1999/2000, 46 (40.4%) of 114 patients with type 1 and 104 (70.7%) of 147 patients with insulin-treated type 2 diabetes were on blood pressure-lowering drugs. Hypertension prevalence in the total population was 57.5%. It was higher in patients with insulin-treated type 2 than in type 1 diabetes (47.4% vs. 78.9%, P<.001). In 1999/2000, the number of patients with type 1, but also type 2, diabetes on blood pressure-lowering agents was higher than in 1994/1995 and 1989/1990. In the whole group, the mean blood pressure improved from 1989/1990 up to 1994/1995 and has remained constant up to the follow-up examination in 1999/2000. In 1999/2000, of those with arterial hypertension, blood pressure was higher than the 140/90-mm Hg target in 17.5% (20/114) of the patients with type 1 and in 42.2% (62/147) of the patients with insulin-treated type 2 diabetes. CONCLUSIONS: The JEVIN trial provides a useful population-based summary of the quality of blood pressure and metabolic control of patients with insulin-treated diabetes. Although the trial demonstrates an impressive improvement in the quality of blood pressure and metabolic control over the last decade, it also shows various problems: In many patients, both with type 1 and type 2 diabetes mellitus, a good blood pressure control (below 140/90 mm Hg) has not been achieved. Moreover, drug therapy, in particular concerning patients with overt nephropathy, is often inappropriate.

Renal Angiotensin receptor type 1 and 2 upregulation in intrauterine growth restriction of newborn piglets.

Epidemiological and experimental studies suggest that intrauterine growth restriction (IUGR) is associated with abnormalities in kidney development which is thought to be linked with alterations causing adult cardiovascular diseases. The renin-angiotensin system (RAS) plays an important role in the development of renal vascular and tubular structures, and is known to be altered by experimentally induced IUGR. These experimental models of IGUR have been criticized because they may have a more severe impact on intrauterine development than that which is normally encountered in humans. Therefore, we asked whether naturally occurring small-for-gestational-age newborn piglets exhibit features of altered RAS activity. We investigated the regional renal expression of angiotensin II type 1 (AT1) and AT2 receptors in normal-weight and IUGR piglets. The AT1 receptor mRNA expression was markedly enhanced in IUGR piglets, in the renal cortex by 64% and in the renal medulla by 52% (p < 0.05, compared with normal littermates). In contrast, mRNA expression for the AT2 receptor was similar in both the normal-weight and IUGR piglets. A significantly higher AT1 receptor protein expression was found in the IUGR piglets (p < 0.05) in the glomeruli, in the proximal and distal tubules, as well as in the collecting ducts by immunohistochemistry. Furthermore, AT2 receptor protein expression was significantly higher in the IUGR piglets (p < 0.05) in the subcapsular nephrogenic zone and in the distal tubules and collecting ducts. Thus, IUGR is accompanied by an upregulation of angiotensin II receptor expression in the kidneys of newborn piglets. This may indicate an alteration of the RAS in newborns suffering from naturally occurring IUGR.

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.

On-line haemodiafiltration versus haemodialysis: stable haematocrit with less erythropoietin and improvement of other relevant blood parameters.

BACKGROUND: Controlled randomised studies to prove improved cardiovascular stability and improved anaemia management during on-line haemodiafiltration (oHDF) are scarce. METHODS: 70 patients were treated with both haemodialysis (HD) and oHDF in a cross-over design during 2 x 24 weeks at a dialysis dose of eKt/V> or =1.2. Patients randomised into group A started on HD and switched over to oHDF, whereas patients in group B began with oHDF and were treated with HD afterwards. Intradialytic morbid events (IME), such as symptomatic hypotension or muscle cramps, were noted in case of appearance. Blood parameters reflecting anaemic status, phosphate status, lipid metabolism, oxidative stress, and accumulation of advanced glycation end products were recorded either monthly or at the end of each study phase. RESULTS: The mean incidence of IME was 0.15 IME per treatment, and there was no statistical difference between oHDF and HD. A higher haematocrit (oHDF 31.5% vs. HD 30.5%, p < 0.01) at a lower erythropoietin dose (oHDF 4,913 vs. HD 5,492 IU/week, p = 0.02) was found during oHDF, when the sequence of HD and oHDF had not been taken into account. For the study groups, the results were less distinct: in group A, a higher haematocrit (HD 30.4% vs. oHDF 32.0%, p < 0.01) at a comparable erythropoietin dose (HD 5,421 vs. oHDF 5,187 IU/week, ns) was observed during oHDF, whereas in group B an identical haematocrit (oHDF 30.8% vs. HD 30.7%, ns) was achieved at a reduced erythropoietin dose (oHDF 4,622 vs. HD 5,568 IU/week, p < 0.01). During oHDF, lower levels of free and protein-bound pentosidine and of serum phosphate were found. CONCLUSION: In contrast to other studies, no benefit regarding cardiovascular stability for oHDF was found, but oHDF could well offer a potential benefit regarding anaemia correction, inflammation, oxidative stress, lipid profiles, and calcium-phosphate product.

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.

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.