Persistent arterial stiffness and endothelial dysfunction following successful pancreas-kidney transplantation in Type 1 diabetes.

OBJECTIVE: Successful simultaneous pancreas-kidney transplantation (SPK) in Type 1 diabetic (T1DM) patients results in improved cardiovascular outcome and survival. However, it is doubtful whether the impairment of cardiovascular and endothelial function in T1DM can be completely reversed. METHODS: Pulse-wave velocity, stroke volume, heart rate, serological markers of endothelial dysfunction (soluble intercellular, vascular cell-adhesion molecules, E-selectin, and plasminogen-activator-inhibitor-1) were measured in 10 T1DM patients after SPK with non-diabetic glucose levels, 10 T1DM patients with poor [T1DM>8; glycated haemoglobin (HbA1c)>8%], and 10 with good glucose control (T1DM<7, HbA1c<7%), in 6 non-diabetic patients after kidney transplantation (KT) and 9 non-diabetic control subjects (CON), matching for major anthropometric characteristics. RESULTS: Pulse-wave velocity was increased in SPK (P < 0.02 vs. CON, KT, T1DM<7) and in T1DM>8 (P < 0.02 vs. T1DM<7). Systolic blood pressure was increased in SPK (P < 0.05 vs. CON). Stroke volume was reduced in SPK, T1DM>8 and T1DM<7 and KT (P < 0.01 vs. CON). Heart rate was elevated in SPK and in T1DM>8 (P < 0.0003 vs. CON and T1DM<7). In SPK, soluble intercellular and vascular cell-adhesion molecules were 100% and 44% higher (P < 0.03 vs. CON), respectively, while plasminogen-activator-inhibitor-1 was decreased in SPK (P < 0.02 vs. CON). CONCLUSION: T1DM patients after SPK experience arterial stiffness, a higher heart-rate and blood pressure, reduced stroke volume and serological signs of endothelial dysfunction. Thus, functional and structural cardiovascular alterations as a result of glucotoxicity, uraemia and hypertension in T1DM might not be completely resolved by SPK.

Postprandial intradialytic dysglycaemia and diabetes in maintenance haemodialysis patients.

BACKGROUND: Although the risk of developing dysglycaemia has been investigated in different communities this incidence is poorly studied in patients on maintenance haemodialysis (MHD). MATERIALS AND METHODS: In a multicentre observational cohort study the occurrence of dysglycaemia was assessed in 239 primary normoglycaemic end stage renal disease (ERSD) patients on MHD. Dysglycaemia (fasting blood glucose > 110 mg dL(-1), > 140 mg dL(-1) 2 h after food intake) or diabetes (fasting blood glucose > 126 mg dL(-1) or > 200 mg dL(-1) at any time) were defined according to WHO criteria and cases were compared with age matched controls within the cohort. RESULTS: Dysglycaemia was found in 82 primary normoglycaemic ESRD patients (34%) within 31 months after initiation of MHD. In 31 of these patients type 2 diabetes was diagnosed. When compared with matched control MHD patients differences in body mass index (BMI), HbA1c and postprandial blood glucose were detectable (P < 0.05). Increments in 0.1% of HbA1c were related with 11% higher odds for dysglycaemia (P = 0.002). In a subgroup of 36 primary normoglycaemic MHD patients who developed dysglycaemia event-free survival was 64%, 53%, 31%, 17% and 11% after 1, 2, 3, 4 and 5 years of haemodialysis treatment. CONCLUSION: Onset of dysglycaemia or diabetes is frequent in ESRD patients after onset of chronic haemodialysis. Routine measurement of blood glucose before and after haemodialysis should be implemented as a standard of care during MHD.

Long-term mortality and incidence of renal dialysis and transplantation in type 1 diabetes mellitus.

AIMS: We investigated long-term mortality and requirement of renal replacement therapy (RRT) in type 1 diabetes mellitus (T1DM) to study risk factors and late complication incidence of T1DM in a prospective cohort study at Lainz Hospital, Vienna, Austria. METHODS: In 1983-1984, T1DM patients [n = 648; 47% females, 53% males; age, 30 +/- 11 yr; T1DM duration, 15 +/- 9 yr; body mass index, 24 +/- 4 kg/m(2); glycated hemoglobin (HbA1c), 7.6 +/- 1.6%] were stratified into HbA1c quartiles [1st, 5.9 +/- 0.5% (range, 4.2-6.5%); 2nd, 6.9 +/- 0.3% (6.6-7.4%); 3rd, 7.9 +/- 0.3% (7.5-8.4%); and 4th, 9.6 +/- 1.3% (8.5-14.8%)]. Twenty years later, both endpoints (death and RRT) were investigated by record linkage with national registries. RESULTS: At baseline, creatinine clearance, blood pressure, and body mass index were comparable among the HbA1c quartiles, whereas albuminuria was more frequent in the 4th quartile (+15%; P < 0.03). After the 20-yr follow-up, 13.0% of the patients had died [rate, 708 per 100,000 person-years (95% confidence interval, 557-859)], and 5.6% had received RRT [311 per 100,000 person-years (95% confidence interval, 210-412)]. Patients with the highest HbA1c values (4th quartile) had a higher mortality rate and a greater incidence of RRT (P < 0.04). In the Cox proportional hazards analysis, age, male gender, increased HbA1c, albuminuria, and reduced creatinine clearance were predictors of mortality (P < 0.05). Predictors of RRT were albuminuria (P < 0.001), reduced creatinine clearance (P < 0.001), and belonging to the 4th HbA1c quartile (P = 0.06). In Kaplan-Meier analysis, mortality was linearly associated with poor glycemia, whereas RRT incidence appeared to rise at a HbA1c threshold of approximately 8.5%. CONCLUSION/INTERPRETATION: In the Lainz T1DM cohort, 13.0% mortality and 5.6% RRT were directly associated with and more frequently found in poor glycemia, showing that good glycemic control is essential for the longevity and quality of life in T1DM.

No effect of naloxone on ventilatory response to progressive hypercapnia in IDDM patients.

The ventilatory response to hyperoxic progressive hypercapnia was examined by comparing 3 test groups: 7 diabetic patients with AN, 8 diabetic patients without AN, and 8 normal control subjects. In each group, a significant linear correlation was found between PaCO2 and VE. The slopes of the regression curves relating PaCO2 to VE were significantly steeper in the healthy control subjects and diabetic patients without AN than in those with AN (P < 0.01). We conclude that the ventilatory response to progressive hypercapnia is reduced in diabetic patients with AN. By analyzing the power spectrum and the amplitude behavior of the diaphragmatic EMG (calculated from the fc and RMS, respectively), we could exclude a disturbance of neural descending pathways and respiratory muscle dysfunction as possible causal mechanisms for the impaired ventilatory response to increasing CO2. By using lung function analysis, causal factors such as alterations in respiratory system mechanics also could be excluded. As diabetes is known to affect the endogenous opioid system, which, in turn, affects the ventilatory response to CO2, naloxone, as a specific opioid antagonist, was administered in all 3 test groups. Naloxone produced a significant increase of ventilatory response to hypercapnia in the healthy control subjects (P < 0.01), but produced no effect in either of the diabetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Polymorphism of complement C4 and susceptibility to IDDM and microvascular complications.

OBJECTIVE: The aim of this study was to investigate whether or not the inherited polymorphism of complement C4 is associated with genetic susceptibility to microvascular complications in IDDM as previously reported. RESEARCH DESIGN AND METHODS: We determined C4 phenotypes in 241 patients with IDDM and 140 healthy control subjects by agarose gel electrophoresis and immunoprecipitation. C4 allotype frequencies were compared between patients and healthy control subjects. In addition, we compared allotype frequencies of 83 patients with nephropathy with those of 80 patients without nephropathy and compared those of 50 patients with proliferative retinopathy with those of 68 patients without retinopathy or background retinopathy. Duration of IDDM in control patients was at least 21 years. RESULTS: Patients and healthy control subjects differed at both the C4A (P < 0.00001) and C4B (P < 0.0005) loci. The C4 null allele C4AQ0 was significantly increased in IDDM patients (26.8 vs. 11.8%, P < 0.005). C4B2 was more frequently observed in patients (14.5 vs. 6.8%, P < 0.05) compared with healthy control subjects. No differences were observed in C4 allotype distribution between patients with and without nephropathy or retinopathy. CONCLUSIONS: These data confirm previous reports of an association between the C4 null allele C4AQ0 and IDDM. Our results do not support an association of the inherited polymorphism of complement C4 with genetic susceptibility to microvascular complications in patients with IDDM.

Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.

The highly atherogenic lipoprotein(a) [Lp(a)] is significantly elevated in patients with renal disease. It is discussed controversially whether Lp(a) concentrations decrease after renal transplantation and whether the mode of immunosuppressive therapy influences the Lp(a) concentrations. In a prospective study the Lp(a) concentrations before and on average 48 months after renal transplantation were measured in 145 patients. The determinants of the relative changes of Lp(a) concentrations were investigated in a multivariate analysis. Patients treated by CAPD showed a larger decrease of Lp(a) than hemodialysis patients, reflecting their markedly higher Lp(a) levels before transplantation. The relative decrease of Lp(a) was higher with increasing Lp(a) concentrations before transplantation in combination with an increasing molecular weight of apolipoprotein(a) [apo(a)]. That means that the relative decrease of Lp(a) is related to the Lp(a) concentration and the apo(a) size polymorphism. With increasing proteinuria and decreasing glomerular filtration rate, the relative decrease of Lp(a) became less pronounced. Neither prednisolone nor cyclosporine (CsA) had a significant impact on the Lp(a) concentration changes. Azathioprine (Aza) was the only immunosuppressive drug which had a dose-dependent influence on the relative decrease of Lp(a) levels. These data clearly demonstrate a decrease of Lp(a) following renal transplantation which is caused by the restoration of kidney function. The relative decrease is influenced by Aza but not by CsA or prednisolone.

Influence of various heparin preparations on lipoproteins in hemodialysis patients: a multicentre study.

Recent studies have indicated controversial effects of low molecular weight heparin (LMWH) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin (UFH). We therefore conducted a cross-sectional multicentre study comparing 153 patients treated with LMWH and 153 patients with UFH, matched for sex, age and diabetes mellitus. Both groups have been treated with LMWH or UFH for six months or longer (14.9 vs. 23.4 months). We observed no differences between the UFH and LMWH treatment groups for total cholesterol, LDL cholesterol, triglycerides, apoB, apoA-IV or Lp(a). The only significant differences were seen for HDL cholesterol and the corresponding apolipoprotein apoA-I, which were significantly higher in the UFH group (HDL cholesterol: 0.97 +/- 0.35 mM/l vs. 0.87 +/- 0.37 mM/l, p < 0.05; apoA-I 1.23 +/- 0.27 g/l vs. 1.15 +/- 0.27 g/l, p < 0.05). We conclude that the results of studies investigating the influence of LMWH on lipid metabolism are as heterogeneous as the substances themselves. This challenges the beneficial influence supposedly had by LMWH preparations on lipid metabolism.

Defective endogenous opioid response to exercise in type I diabetic patients.

Plasma beta-endorphin (beta-E) concentration was determined before, during, and after a standardized incremental exercise test to maximal capacity in eight type I diabetic patients and eight normal control subjects. Diabetic patients were studied under normoglycemic and hyperglycemic conditions in a single-blind random fashion to differentiate between the effects of acute hyperglycemia and of diabetes per se on the beta-E response to exercise. The perceived magnitude of leg effort elicited by exercise was evaluated using a category scale. Whereas plasma beta-E concentrations increased in control subjects with increasing workload, causing significantly higher beta-E levels at the end of exercise than at the beginning (P < .001), no such increase could be observed in the diabetic patients under normoglycemic and hyperglycemic conditions. In addition, baseline plasma beta-E concentrations were significantly lower in normoglycemic (P < .01) and hyperglycemic (P < .001) diabetic patients than in control subjects. Even during the recovery period, patients' beta-E levels remained significantly lower than those of control subjects. At submaximal levels of power output, the perceived intensity of leg effort was significantly higher in normoglycemic and hyperglycemic diabetic patients than in control subjects. We conclude that in type I diabetic patients, the ability of the endogenous opioid system to respond to exercise-induced stress is impaired under hyperglycemic and even under normoglycemic conditions. Considering the effect of endogenous opioids on stress tolerance, such changes may compromise exercise performance in diabetic patients.

Safety and tolerability of a multidose formulation of epoetin beta in dialysis patients. Collaborative Study Group.

AIM: Previous studies in healthy volunteers and renal patients have demonstrated the favorable tolerability of a new multidose formulation of epoetin beta. The aim of this open, multicenter study was to further assess the safety, tolerability and efficacy of this formulation ofepoetin beta in patients with end-stage renal disease (ESRD). MATERIALS AND METHODS: 375 adult patients receiving maintenance epoetin therapy for renal anemia were switched to the multidose formulation of epoetin beta for 12 weeks, using the same dosage and route of administration. RESULTS: Adverse events were experienced by 123 patients (33%), most commonly hypertension (5.6%) and hypotension (4.5%). Few patients (2%) were prematurely withdrawn because of tolerability concerns. No clinically relevant changes in blood pressure or laboratory variables were observed. Compared with baseline, hemoglobin and hematocrit values remained essentially unchanged during treatment with this new formulation of epoetin beta. No changes in iron metabolism parameters were apparent, and nearly all patients (94%) did not require blood transfusions during the study. CONCLUSION: The results of this study indicate that the multidose formulation of epoetin beta is safe and well tolerated in patients with ESRD. Moreover, switching patients to this new formulation of epoetin beta does not compromise therapeutic efficacy.

Eicosanoid precursors: potential factors for atherogenesis in diabetic CAPD patients?

Prostaglandins, thromboxanes, and other eicosanoids represent a widespread lipid-mediator system for intercellular signalling, and, hence, have multiple cellular actions. Thus it is not surprising that numerous events in the pathogenesis of atherosclerosis are associated with an altered formation of eicosanoids. To reconsider the availability of eiconsanoid precursors as one possible cause of atherogenesis, the dietary intake and the serum concentrations of arachidonic acid (AA) and eicosapentaenoic acid (EPA) were determined in patients with high risk for atherosclerosis on continuous ambulatory peritoneal dialysis (CAPD) with and without diabetes in comparison to healthy controls and diabetic patients without late complications. The factor AA/EPA in serum was created as a marker for the atherosclerosis risk. The setting was in a CAPD unit in one city hospital. There were 26 CAPD patients [9 with insulin-dependent diabetes mellitus (IDDM), 9 with noninsulin-dependent diabetes mellitus (NIDDM), and 8 without diabetes], 27 IDDM without late complications, and 41 healthy control persons. The AA levels in serum were significantly higher in all of the CAPD groups. In contrast, the EPA concentrations in serum were significantly lower in the CAPD groups, with the lowest EPA levels found in the CAPD-IDDM group. Therefore, the factors AA/EPA in serum were significantly higher in all of the CAPD groups, and again significantly higher in the CAPD-IDDM group than in the other CAPD groups. No differences in the amount of dietary intake of AA existed between the groups. The daily intake of EPA was significantly highest in the control group. Higher concentrations of AA and a lack of n-3 fatty acids lead in the presence of a reduced prostaglandin I2 biosynthesis, to a higher formation rate of potentially proatherogenic metabolites such as thromboxane A2, a vasoconstricting and platelet aggregating agent. Thus, the quotient AA/EPA could possibly be used as a marker of atherogenicity in the future.

[Prevalence of cardiac autonomic neuropathies in uremia and diabetes mellitus]. / Prävalenz der kardialen autonomen Neuropathie bei Urämie und Diabetes mellitus.

In the absence of relevant data, the prevalence of cardiac autonomic neuropathy was investigated in patients with diabetes mellitus or uremia due to other causes and diabetic patients with endstage renal failure. 117 patients (40 on a dialysis program without diabetes, 32 with diabetes mellitus type 1 but no nephropathy, 16 type 1 and 13 type 2 diabetic uremic patients, 16 diabetic patients with a kidney graft) and 25 healthy control subjects underwent assessment of the cardiorespiratory reflexes. The evaluation of parasympathetic damage was of particular interest. Definite parasympathetic dysfunction was detected in 32% of the non-diabetic uremic and in 19% of the non-uremic type 1 diabetic patients. Furthermore, 88% of type 1 and 77% of type 2 diabetic patients on dialysis and 75% of diabetic patients after kidney transplantation had evidence of autonomic neuropathy.

[Alcoholic ketoacidosis--3 episodes in one patient]. / Beobachtungen zur alkoholischen Ketoazidose--3 Episoden bei einem Patienten.

3 episodes of alcoholic ketoacidosis were observed in one female patient over a period of 19 months. The clinical picture consisted of vomiting, dehydration, hyperventilation and abdominal pain. Predominant laboratory findings were acidosis (pH less than 7) and hyperglycaemia, with blood glucose values of 354, 330 and 147 mg/dl. This disorder is an important cause of metabolic acidosis, but especially in the German literature there are only rare reports on this issue. The picture of ketoacidosis in mostly chronically malnourished alcoholics reflects not only the complex abnormalities of acid-base balance caused by excessive cumulation of ketoacids, but also the related severe depletion of electrolytes and extracellular volume. Adequate acute therapy (as for diabetic ketoacidosis) and thorough follow-up treatment of any concurrent conditions result in rapid reversal of the syndrome in most cases. Since there are few reports of repeated episodes in one patient, an overview of this disorder is presented concerning management and differential diagnosis of the basis of our case report.

[Detection of an insulinoma in pregnancy--a rare cause of hypoglycemia]. / Nachweis eines Insulinoms in der Schwangerschaft--eine seltene Hypoglykämieursache.

An insulinoma was diagnosed in a 26 year-old woman who suddenly went into hypoglycemic coma in the 38th week of an apparently uncomplicated pregnancy. On review of the history it became apparent that symptoms due to hypoglycemia had been present since the 16th week of pregnancy. Continuous intravenous infusion of glucose was administered and the patient was delivered of a healthy child 5 days later. Investigations revealed 2 insulinoma nodules in the tail of the pancreas which were successfully removed 2 weeks post partum.

A prospective study of predictors for foot ulceration in type 2 diabetes.

One hundred eighty-seven type 2 diabetic patients without a history of foot ulceration were followed for a mean period of 3.6 years to investigate the incidence of foot ulceration in a diabetes cohort and to analyze risk factors for foot ulceration by multivariate means. During the study, 10 subjects developed 18 forefoot ulcerations. In multivariate logistic regression, significant predictors for foot ulceration were an elevated vibration perception threshold (VPT) (relative risk [RR] = 25.4), an increased plantar pressure (RR = 6.3), and daily alcohol intake (RR = 5.1). This is the first prospective study to demonstrate plantar pressure and daily alcohol intake as predictors of foot ulceration among patients without previous ulceration. Further, VPT could be confirmed as the strongest predictor for foot ulceration, and it was clearly demonstrated that the more pronounced severity of complications occurred among subjects with elevated VPT.

A novel laboratory set-up for investigating surface and interface reactions during short term annealing cycles at high temperatures.

High temperature oxidation is an important research discipline that covers many topics in steel manufacture and modern energy research. To account for the need of adjusting accurate processing conditions, recent developments of the high temperature laboratory setup at the Max-Planck-Institut für Eisenforschung GmbH will be presented. The experimental assembly has been optimized to investigate surface and interface reactions at elevated temperatures in low oxygen activity gases, covering a large field of experimental possibilities. Many efforts have been taken to enable an accurate control and in situ monitoring of process conditions such as gas flow, gas composition, impurity content, and mass change of the sample.

Postprandial blood glucose level in maintenance hemodialysis patients predicts post-transplant-diabetes-mellitus.

Post-transplant-diabetes-mellitus (PTDM) is a frequent complication after kidney transplantation. One-hundred-and-seven patients with kidney transplantation were screened for the occurrence of PTDM. Of these, full data sets from 49 subjects were available with documented glucose concentrations during maintenance hemodialysis (MHD) and regular clinical follow-up of 7-34 months. For assessment of glucose metabolism the response to a standard meal during MHD was used in normoglycemic patients based on fasting blood glucose. Abnormal postprandial blood glucose concentration was defined as >140 mg/dl 2 h after food intake.Twelve end stage renal disease patients had abnormal postprandial blood glucose on MHD. All 12 subjects but also four MHD patients with normal postprandial and fasting blood glucose values developed PTDM. Multivariate Cox-regression analysis revealed that abnormal postprandial blood glucose is a strong predictor for PTDM (Hazard ratio: 42.3 (IQR: 7.9-227.2); p<0.001). Fasting blood glucose (94 vs. 100 mg/dl) was not different between MHD patients who did (n=16) or did not (n=33) develop PTDM.This study suggests that measurement of postprandial blood glucose during MHD identifies patients who develop PTDM after kidney transplantation. It should be used for screening of patients at risk.

[CAPD (continuous ambulatory peritoneal dialysis) in diabetic nephropathy: overview and general practice in the Lainz Hospital since 1982]. / CAPD bei diabetischer Nephropathie: Uberblick und Praxis im Krankenhaus Lainz seit 1982.

While there is progress in management of newly-diagnosed diabetic patients, treatment of diabetes and prevention of comorbid conditions, nephrologists are progressively confronted with the picture of fully established micro- and macrovascular disease. Experience with CAPD in patients with diabetes mellitus in the hospital Vienna-Lainz from 1982 to 8/1999 was analyzed and outcome data are presented. During this period 139 patients were treated with CAPD as primary renal replacement therapy, 41 with diabetes Type 1 and 47 with diabetes Type 2. Survival rate after 10 years of treatment (including transplantation and change to hemodialysis due to technical failure of CAPD) was 50% in type 1 diabetes and 8% in type 2 diabetes. In 73% of patients with type 1 diabetes a kidney or kidney-pancreas transplantation was performed. In contrast, only 11% of type 2 diabetic patients were eligible for kidney transplantation. These long-term data implicate further attempts in reducing the incidence of diabetic nephropathy and later on renal failure. Furthermore, screening and aggressive treatment for atherosclerotic complications are necessary to improve the prognosis in this patient cohort.