Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis.

OBJECTIVES: To review the evidence from controlled clinical trials of neonates given equal daily aminoglycoside doses as extended interval dosing (dosage interval typically 24 hours in term and 36-48 hours in immature neonates) compared with traditional dosing (dosage interval typically 8-12 hours in term and 12-24 hours in immature neonates). DESIGN: Systematic review and meta-analysis of controlled trials found in electronic databases, trial registers, and references in reviews and selected trials. SETTINGS: The selected trials were blinded and assessed for methodological quality. Each trial's own predefined criteria for treatment failure, nephrotoxicity, ototoxicity, and therapeutic serum drug concentrations were used. SUBJECTS: Controlled trials of neonatal aminoglycoside treatment in which equal aminoglycoside daily doses were given at traditional and extended dosage intervals. MAIN OUTCOME MEASURES: Serum drug concentrations outside the therapeutic range. Treatment failure and toxicity. RESULTS: Sixteen trials involving 823 neonates met the inclusion criteria for the systematic review. Twelve trials involving 698 neonates were included in the meta-analysis of the pharmacokinetics. Compared with traditional dosing, extended interval dosing was associated with a significantly lower risk of both peak (summary risk ratio 0.50, 95% confidence interval 0.26 to 0.94) and trough (0.36, 0.25 to 0.56) serum drug concentrations outside the therapeutic range. Accurate information on treatment failure was obtained in nine trials involving 555 neonates. One trial reported treatment failure. In this trial two neonates in the traditional dosing group did not respond to treatment within 72 hours. Nephrotoxicity was investigated in 589 neonates in 12 trials and ototoxicity in 210 neonates in four trials, with no significant differences between the two dosing regimens. CONCLUSIONS: Extended interval dosing of aminoglycosides in neonates is safe and effective, with a reduced risk of serum drug concentrations outside the therapeutic range.

New semiquantitative dipstick test for microalbuminuria.

OBJECTIVE: We compared a new semiquantitative dipstick test for microalbuminuria (Micral-Test) with a quantitative immunoturbidimetric method. RESEARCH DESIGN AND METHODS: This correlation study was performed at a pediatric and medical outpatient clinic at a university hospital. Overnight urine samples containing less than 200 mg/L albumin from 186 diabetic patients were analyzed. RESULTS: The correlation coefficient between the new semiquantitative method and the immunoturbidimetric reference method was 0.82. Elevated albumin concentration was defined as greater than 20 mg/L albumin in overnight urine, and the prevalence of samples with values above this level was 28%. By this definition, the Micral-Test assay level greater than or equal to 20 mg/L had a sensitivity of 92.3% and a specificity of 82.1%. Of the diabetic subjects, 84.9% were correctly classified as having elevated urinary albumin concentration or not. CONCLUSIONS: The Micral-Test is useful for in-clinic screening for elevated urinary albumin concentration and monitoring the development of urinary albumin excretion in the low microalbuminuric range.

Influence of insertion/deletion polymorphism in the ACE-I gene on the progression of diabetic glomerulopathy in type 1 diabetic patients with microalbuminuria.

OBJECTIVE: To investigate the influence of the insertion/deletion polymorphism of the ACE gene on the progression of early diabetic glomerulopathy in patients with and without antihypertensive treatment (AHT). RESEARCH DESIGN AND METHODS: There were 30 microalbuminuric patients with >5 years of type 1 diabetes who had renal biopsies taken at baseline and after 26-48 months of follow-up. Of the 30 patients, 13 (4 with II genotype and 9 with ID and DD genotypes) were randomized to AHT (enalapril or metoprolol) during the study. The ACE genotype was determined by a polymerase chain reaction. Glomerular structural changes were measured by stereological methods. RESULTS: Of the patients, 8 had the II genotype, 19 had ID genotype, and 3 had DD genotype. During the study, basement membrane thickness, matrix star volume, and the overall diabetic glomerulopathy index were increased in patients with ID and DD genotypes only (P < 0.001, P = 0.01, P < 0.001, respectively). Among those with ID and DD genotypes, progression of basement membrane thickening and diabetic glomerulopathy index were increased in those without AHT, as compared with the antihypertensive treated patients (P < 0.001, P = 0.02, respectively). In multivariate analysis, the ACE genotype had an independent influence on the progression of basement membrane thickening (P = 0.01), when AHT (P < 0.001) and the mean HbAlc during the study (P < 0.001) were also taken into account. ACE genotype tended to be independently associated with the diabetic glomerulopathy index (P = 0.05). CONCLUSIONS: Microalbuminuric type 1 diabetic patients carrying the D-allele have an increased progression of diabetic glomerulopathy. Presence of this allele and no AHT seems to enhance this process. Larger studies are needed to confirm the clinical significance of our findings.

Severity of glomerulopathy predicts long-term urinary albumin excretion rate in patients with type 1 diabetes and microalbuminuria.

OBJECTIVE: To investigate whether the degree of glomerular structural lesions in young patients with type 1 diabetes and microalbuminuria was associated with urinary albumin excretion rate (AER) 6 years later and whether the AER level was influenced by blood glucose control, blood pressure, or glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: There were 17 young adults with type 1 diabetes and microalbuminuria, 8 men and 9 women with mean age 20 years (95% CI: 18-22) and duration of diabetes of 11 years (10-13), who participated in a 6-year prospective study. Kidney biopsies (measurements of basement membrane thickness [BMT] and mesangial and matrix volume fractions) and GFR were performed at baseline. AER and HbA1c were measured at least three times a year and blood pressure once a year. RESULTS: In a multivariate analysis, baseline BMT and mean 6-year HbA1c contributed significantly to AER at the end of the study (R2 = 0.69, P < 0.01). When mesangial volume fraction replaced BMT as the independent variable, this parameter and AER at baseline predicted the AER at 6 years (R2 = 0.55, P < 0.55). Mesangial volume fraction and BMT (in separate analysis) contributed significantly to change in AER during the study. During the study, neither AER (30 micrograms/min [19-40] to 16 micrograms/min [7-90]) nor blood pressure (96 mmHg [92-102] to 95 mmHg [91-98]) changed significantly in the group. However, HbA1c was reduced from 10.3 (9.6-11.0) to 8.4% (7.8-9.1) (P < 0.01). CONCLUSIONS: In young patients with microalbuminuria, the long-term urinary AER was predicted by the degree of glomerular structural changes and associated with blood glucose control, but not with blood pressure or GFR.

The advanced glycation end product Nepsilon-(carboxymethyl)lysine is increased in serum from children and adolescents with type 1 diabetes.

OBJECTIVE: To investigate whether children and adolescents with type 1 diabetes have increased serum levels of the glycoxidation product Nepsilon-(carboxymethyl)lysine (CML) at an early stage of the disease. RESEARCH DESIGN AND METHODS: The serum levels of CML in 38 patients with type 1 diabetes aged 14+/-3.2 (mean+/-SD) years were compared with those in 26 control subjects aged 16+/-1.7 years. The mean duration of diabetes was 5+/-4.7 years, ranging from 0.5 to 15 years. The mean levels of HbA1c were 10.3+/-2.5% in the patient group. The serum levels of CML were measured using a monoclonal anti-CML antibody in a fluoremetric immunoassay. Serum protein levels of advanced glycation end products (AGEs) were assayed using a polyclonal antibody from rabbit immunized with AGE-RNase (pAGE). RESULTS: The serum levels of CML and pAGE were significantly increased in the patient group versus the control group: 1.08 (0.45-2.97) U/ml CML (median 10-90 percentiles) vs. 0.70 (0.36-1.79) U/ml CML, P < 0.03, and 6.6 (5.1-9.9) U/ml pAGE vs. 5.5 (3.7-8.2) U/ml AGEs, P < 0.01. A significant relationship between CML and pAGE was found in the IDDM group, r = 0.76, P < 0.001. The CML levels were not associated with the HbAlc levels (n = 23, r = -0.02, NS), cholesterol levels (n = 21, r = 0.07, NS), age, sex, or diabetes duration. CONCLUSIONS: Serum levels of CML are increased in patients with type 1 diabetes. This increase precedes the development of micro- and macrovascular complications.

Hydroperoxides in plasma are reduced by intensified insulin treatment. A randomized controlled study of IDDM patients with microalbuminuria.

OBJECTIVE: An association between reactive oxygen species and diabetic micro- and macrovascular complications has been proposed. In the present study, we have examined the effect of an improved blood glucose control on plasma levels of hydroperoxides in patients with IDDM. RESEARCH DESIGN AND METHODS: Subjects included 30 young IDDM patients with microalbuminuria who were randomized to receive either continuous subcutaneous insulin infusion (CSII) by a portable insulin pump (n = 15) or conventional insulin treatment (CIT) (n = 15) for 24 months. Plasma levels of hydroperoxides were measured by the ferrous oxidation with Xylenol Orange, version 2 (FOX2) assay. This method measures total lipid hydroperoxides and, unlike other methods, does not suffer from extraction losses. RESULTS: The mean HbA1c level was lower in the CSII group at the end of the study than in the CIT group: (mean [95% CI]) 8.6 (8.1-9.1) vs. 9.6 (9.0-10.3)%, respectively (P < 0.002). The level of plasma hydroperoxides was very similar at the start of the study but was significantly lower in the CSII group compared with the CIT group at the end of the study: 2.9 (2.1-3.7) vs. 4.3 (3.2-5.4) mumol/l, respectively (P < 0.02). In the CSII group, hydroperoxides were reduced by 31% from baseline (P < 0.001), whereas there was no change in levels of hydroperoxides in the CIT group. Mean hydroperoxide levels correlated with mean HbA1c during the study (r = 0.39, P < 0.04). Hydroperoxide levels were associated with the levels of microalbuminuria (r = 0.45, P < 0.02). CONCLUSIONS: This study provides support for the hypothesis that hyperglycemia is an important factor in the generation of hydroperoxides, and, thus, reactive oxygen species, in the circulation of IDDM patients.

Long-term studies of the juxtaglomerular apparatus in young microalbuminuric type 1 diabetic patients.

AIM: To determine the long-term changes of the juxtaglomerular apparatus in incipient diabetic nephropathy. METHODS: Three renal needle biopsies were performed on 15 young type I diabetic patients with microalbuminuria; at baseline and after an average of 2.4 and 8.2 years. Using light microscopy, 1 microm serial sections of the plastic-embedded biopsies were investigated and volumes of the juxtaglomerular apparatus and glomerulus and areas of the macula densa and lumina of the afferent and efferent arterioles were measured. RESULTS: From baseline to second follow-up there was a significant decrease in JGA relative to glomerular volume. There was an increase in luminal area of the efferent arteriole which was paralleled by (non-significant) changes in the afferent arteriole. CONCLUSION: Over a period of 8.2 years JGA size remained stable, but decreased relative to glomerular size. Also, an increase in luminal area was noted in efferent arterioles. This may be due to increased single nephron blood flow secondary to nephron loss.

On glomerular structural alterations in type-1 diabetes. Companions of early diabetic glomerulopathy.

Glomerular structural modifications were measured in kidney biopsies from two follow-up studies in type-1 diabetic patients with microalbuminuria and in kidney donors. Stereologic methods were used to obtain data on glomerular composition and absolute quantities per glomerulus to supplement data on diabetic glomerulopathy previously published. Diabetic patients at baseline (n=37) showed significant changes compared with controls (n=11). The volume fraction of tuft/glomerulus was increased, the proportion of capillary surface facing peripheral basement membrane was decreased (0.72+/-0.04 vs 0.77+/-0.03, P=0.0008), the ratio of mesangial surfaces, urinary/capillary, was decreased (0.67+/-0.17 vs 1.11+/-0.28, P<10(-4)), and the average capillary diameter was increased (8.9+/-0.9 microm vs 7.5+/-1.0 microm, P=0.0002). The total volume of mesangial extracellular material per glomerulus was increased (P=0.01), whereas glomerular volume was not significantly different from controls. Follow-up biopsies after antihypertensive treatment with ACE-inhibitor (n=7) or beta-blocker (n=6; 36-48 months) and after intensive insulin treatment (n=7; 24-33 months) showed no change. In a conventionally treated group (n=9), the glomerular volume, the volume of extracellular material/glomerulus, and the capillary length increased. The mean capillary diameter did not correlate with the glomerular volume. In conclusion, the development of diabetic glomerulopathy entails structural modifications of the glomerular tuft. Antihypertensive and intensified insulin treatment seem to slow the progression of ultrastructural changes.

The juxtaglomerular apparatus in young type-1 diabetic patients with microalbuminuria. Effect of antihypertensive treatment.

BACKGROUND: Our goal was to investigate the effect of antihypertensive drugs on the juxtaglomerular apparatus (JGA) in young type-1 diabetic patients with microalbuminuria. METHODS: Twelve patients were allocated to treatment with either an angiotensin-converting enzyme inhibitor (group 1, six subjects) or a beta-receptor blocker (group 2, six subjects). A comparable group of nine patients without antihypertensive treatment provided reference values (group 3, nine subjects). Renal biopsies were taken at baseline and after a median of 40 months (groups 1 and 2) and 30 months (group 3). Using light microscopy with 1microm serial sections of the plastic-embedded biopsies, volumes of the JGA and glomerulus and areas of the macula densa and lumina of the afferent and efferent arterioles were obtained. RESULTS: A significant decrease of the volume of the JGA (P=0.026) and of the volume of the JGA relative to that of its corresponding glomerulus (P=0.0005) was noted in the reference group only. Negative correlations existed between the increase in the luminal area of the afferent arteriole and mean diastolic blood pressure in the study period in group 1 (P=0.024) and group 2 (P=0.032). CONCLUSIONS: Our results showed that a decrease in the size of the JGA is offset by antihypertensives. The negative correlation between the change in the luminal area of the afferent arteriole and mean diastolic blood pressure in groups 1 and 2 suggest that renal protection in antihypertensive treatment may be through a better constriction of the afferent arteriole protecting the glomerulus from systemic blood pressure.

Glomerular volume and the glomerular vascular pole area in patients with insulin-dependent diabetes mellitus.

The vascular pole area (VPA) and glomerular volume were measured in renal biopsies from 9 insulin-dependent diabetes mellitus (IDDM) patients with normal albumin excretion rate (IDDM group 1), 38 IDDM patients with albumin excretion rate > 15 micrograms/min (IDDM group 2) and 10 living kidney donors (ND). The volume of individual glomeruli was estimated as the sum of profile areas factored by the measured distance between levels, t approximately 10 microns, and VPA as the sum of chords multiplied by t. Mean glomerular volume was increased in IDDM patients but reached statistical significance only in IDDM group 2 (P = 0.002 vs ND). VPA was significantly different among the groups, mean (CV%) was 2036 (29) microns2 in ND, 3555 (34) micron2 in IDDM group 1, and 3528 (48) microns2 in IDDM group 2, p = 0.004 and 0.001, IDDM versus ND. VPA calculated as a percentage of the surface area of the corresponding glomerulus was 2.4 (23)% in ND, 3.4 (27)% in IDDM group 1, and 3.3 (42)% in IDDM group 2; P = 0.007 and 0.01, IDDM versus ND. The intra-biopsy coefficient of variation was high (20-35%) and of the same order in all groups for all three measurements. Glomerular volume and absolute as well as relative size of VPA showed a positive correlation with estimates of mesangial expansion in IDDM group 2 and the VPA showed a negative correlation with GFR. Thus, part of the enlargement may represent a compensatory phenomenon triggered by the development of structural and functional abnormalities in the diabetic kidney.

Advanced glycation end products in serum predict changes in the kidney morphology of patients with insulin-dependent diabetes mellitus.

The biochemical mechanisms that cause the development and progression of diabetic nephropathy are unknown. Advanced glycation end products (AGEs) might play a role, as shown by increased levels of tissue-bound and circulating AGEs that correlate with the severity of diabetic nephropathy. The aim of the present study was to investigate if circulating AGEs predict the progression of morphological pathology in patients with diabetic nephropathy. We have developed an immunoassay to determine serum levels of AGEs. In a prospective clinical trial of young insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria, kidney biopsies were taken at baseline and after 24 to 36 months. The biopsies were analyzed for structural changes in the glomeruli by quantitative morphometry (electron microscopy). We have retrospectively analyzed serum AGEs. The mean serum level of AGEs at the start of the study was 18.7 U/mL (95% confidence interval [CI], 16.9 to 20.5). A positive correlation between serum AGE levels at the start of study and changes from baseline to follow-up study in basement membrane thickness (r = .56, P < .02) and matrix/glomerular volume fraction (r = .57, P < .02) was demonstrated. In a stepwise regression analysis with changes in the matrix/glomerular volume fraction as the dependent variable, serum AGE levels at the start of the study proved to be a significant independent variable (P < .02), whereas the mean hemoglobin A1c (HbA1c) or HbA1c at the start was not. This study shows that serum AGEs predict the progression of early morphological kidney damage during 2.5 years in patients with IDDM.

Detection and management of diabetic glomerulopathy in children and adolescents with insulin-dependent diabetes mellitus: need for improved knowledge and better care.

Current modalities of detection and management of incipient diabetic nephropathy in childhood and adolescence are summarized and the open questions outlined. In particular, the predictive value of microalbuminuria for later nephropathy in adolescents is examined. Microalbuminuria is not as strong a predictor as suggested in earlier studies - recent studies show up to 50% of microalbuminuria can revert to normal. We advocate that the association of well-established risk markers and promoters of renal injury, including degree and tracking of albuminuria, glycemic control, blood pressure changes, incipient retinopathy and genetic background, allow more precise assessment of the individual risk of developing nephropathy and the decision to start pharmacological intervention. The major impact of strict glycemic control to prevent the development and progression of diabetic nephropathy is emphasized, as well as the need for a multidisciplinary team to optimize the care of pediatric diabetic patients. We discuss other therapeutic options, i.e. angiotensin-converting enzyme inhibitors (ACE-Is), moderate dietary protein intake, and other drugs. ACE-Is may provide a second line intervention in a well selected, high-risk subgroup of microalbuminuric diabetic adolescents.

Serum Lp(a) lipoprotein concentrations in insulin dependent diabetic patients with microalbuminuria.

OBJECTIVE: To compare the serum concentrations of lipoproteins and apolipoproteins in insulin dependent diabetic patients with and without microalbuminuria. DESIGN: Cross sectional study. SETTING: Paediatric and medical outpatient clinic at a university hospital. PATIENTS: 76 insulin dependent diabetic patients: 41 with microalbuminuria (20 males, 21 females) and 35 controls without microalbuminuria (18 males, 17 females). The two groups were similar with respect to age, duration of disease, and haemoglobin A1c concentrations before the study. MAIN OUTCOME MEASURES: Serum concentrations of Lp(a) lipoprotein, total cholesterol, high density lipoprotein cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, and apolipoproteins A-I, A-II, and B. RESULTS: Median serum Lp(a) lipoprotein concentration was 10.0 mg/100 ml in the microalbuminuric group and 4.9 mg/100 ml in the control group (p = 0.007). 17 (41%) of the microalbuminuric patients and five (14%) of the control patients had Lp(a) lipoprotein values above the upper quartile of a normal population. Median serum triglycerides concentrations in the microalbuminuric and control groups were 1.15 mmol/l and 0.88 mmol/l respectively (p = 0.03). Median very low density lipoprotein cholesterol concentration was 0.52 mmol/l in the microalbuminuric group and 0.40 mmol/l in the control group (p = 0.03). No significant differences in serum concentrations of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, or apolipoproteins A-I, A-II, and B were found between the groups. CONCLUSIONS: Serum concentrations of Lp(a) lipoprotein are twice as high in insulin dependent diabetic patients with microalbuminuria as in those without microalbuminuria. Increased concentrations of Lp(a) lipoprotein might partly explain the increased morbidity and mortality from cardiovascular disease observed among patients with diabetic nephropathy.

Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway.

AIMS/HYPOTHESIS: We examined long-term total and cause-specific mortality in a nationwide, population-based Norwegian cohort of patients with childhood-onset type 1 diabetes. MATERIALS AND METHODS: All Norwegian type 1 diabetic patients who were diagnosed between 1973 and 1982 and were under 15 years of age at diagnosis were included (n=1,906). Mortality was recorded from diabetes onset until 31 December 2002 and represented 46,147 person-years. The greatest age attained among deceased subjects was 40 years and the maximum diabetes duration was 30 years. Cause of death was ascertained by reviews of death certificates, autopsy protocols and medical records. The standardised mortality ratio (SMR) was based on national background statistics. RESULTS: During follow-up 103 individuals died. The mortality rate was 2.2/1000 person-years. The overall SMR was 4.0 (95% CI 3.2-4.8) and was similar for males and females. For ischaemic heart disease the SMR was 20.2 (7.3-39.8) for men and 20.6 (1.8-54.1) for women. Acute metabolic complications of diabetes were the most common cause of death under 30 years of age (32%). Cardiovascular disease was responsible for the largest proportion of deaths from the age of 30 years onwards (30%). Violent death accounted for 28% of the deaths in the total cohort (35% among men and 11% among women). CONCLUSIONS/INTERPRETATION: Childhood-onset type 1 diabetes still carries an increased mortality risk when compared with the general population, particularly for cardiovascular disease. To reduce these deaths, attention should be directed to the prevention of acute metabolic complications, the identification of psychiatric vulnerability and the early detection and treatment of cardiovascular disease and associated risk factors.

Low cumulative incidence of proliferative retinopathy in childhood-onset type 1 diabetes: a 24-year follow-up study.

AIMS/HYPOTHESIS: We estimated cumulative incidence of proliferative diabetic retinopathy (PDR) and risk factors for developing diabetic retinopathy (DR) in childhood-onset type 1 diabetes. MATERIALS AND METHODS: A sample of 294 patients with childhood-onset type 1 diabetes (<15 years) diagnosed in Norway between 1973 and 1982 was examined for retinopathy at baseline between 1989 and 1990 and at follow-up from 2002 to 2003. At follow-up, mean age was 33 years (range: 21-44), mean diabetes duration 24 years (19-30) and total person-time contributed 7,152 person-years. Retinal photographs were taken at baseline and follow-up. Associations between baseline factors and PDR were estimated using Cox regression models. RESULTS: Overall, 262 of 294 (89.1%) developed DR from diabetes onset, of whom 31 developed PDR. The 25-year cumulative incidence of PDR was 10.9% (95% CI 7.3-14.5). Among 194 without retinopathy at baseline, 163 (84%) developed DR and nine (5%) progressed to PDR. Among 97 patients with non-proliferative DR at baseline, 19 (20%) progressed to PDR. Significant predictors for developing PDR were retinopathy at baseline (relative risk [RR]=3.71, 95% CI 1.59-8.68), HbA(1c) (RR=2.05, 1.44-2.93), and triglycerides (RR=1.55, 1.06-1.95). CONCLUSIONS/INTERPRETATION: Nine out of every ten patients diagnosed with type 1 diabetes developed DR, but only one out of ten developed PDR within their first 25 years of diabetes duration. The cumulative incidence of PDR is lower than previously reported from other countries. Potentially modifiable risk factors predict the development of DR and PDR.

[Primary renal tubular dysfunction and short stature in children]. / Primaer renal tubulaer dysfunksjon og kortvoksthet hos barn.

Impaired growth in children without constitutional growth delay or known chronical disease is often linked to endocrine or gastrointestinal disorders. A rare cause is primary renal tubular dysfunction. A brother and a sister who were diagnosed as having Barter's syndrome, later corrected to Gitelman's syndrome, are presented. Both of these syndromes include hypokalemia, hypochloremia, metabolic alkalosis, usually hypomagnesemia, increased activation of the renin-angiotensin-aldosterone system, normal blood pressure and impaired growth. Patients with the classical Bartter's syndrome are treated with potassium chloride and a prostaglandin synthesis inhibitor, and patients with Gitelman's syndrome with magnesium chloride supplementation. We emphasize that measurement of serum electrolytes should be included in the investigation of children with impaired growth.

[Accidental administration of racemic adrenaline. Three life-threatening cases after intravenous injection in children]. / Feiladministrering av racemisk adrenalin. Tre livstruende tilfeller etter intravenøs injeksjon hos barn.

The inhalation of racemic adrenalin is an important part of the treatment of inflammatory airway obstruction in children. In Norway during the last few years there have been several cases of adrenal solutions intended only for inhalation being accidentally administered as intravenous injections. The solution for inhalation contains an adrenalin concentration 110 times greater than the adrenalin intended for emergency use (0.1 mg/ml). The instant consequences of intravenous injections of inhalation adrenalin include arterial hypertension followed by hypotension, cardiac ischemia and cardiac insufficiency, pulmonary oedema, and respiratory failure and the need for artificial ventilation. The clinical picture in the three patients we describe was very dramatic. The injected doses were 0.16-1.1 mg l-adrenalin per kg body weight. All children survived without sequelae. In order to reduce the risk of accidentally administering intravenous injections of adrenalin intended for inhalation a set of guidelines is being proposed.

Follow-up study of glomerular dimensions and cortical interstitium in microalbuminuric type 1 diabetic patients with or without antihypertensive treatment.

BACKGROUND: A decrease in urinary albumin excretion is regularly seen with antihypertensive treatment in patients with diabetic nephropathy. Our study concerns structural data obtained by light microscopy in baseline and follow-up biopsies in antihypertensive treated patients and in a reference group. METHODS: Microalbuminuric type 1 diabetic patients with diabetes duration of 6-16 years were studied. Two groups, allocated to treatment with either angiotensin-converting enzyme-inhibitor (group 1, n=6) or beta-blocker (group 2, n=6) after the baseline biopsy, were studied in parallel, whereas the reference group (group 3, n=9), without antihypertensive treatment, was part of a previously completed study. The renal plastic-embedded biopsies were serially sectioned (1 microm), the sections being used for determining glomerular volume, vascular pole area, and interstitial space expressed as fraction of tubular cortex. RESULTS: A significant increase in glomerular volume (P=0.04) was seen in group 3 only. Vascular pole area (VPA) and VPA relative to calculated glomerular surface did not show significant changes in any of the groups, only a tendency to increase in VPA in group 3 (P=0.051). The increase in VPA correlated with systolic blood pressure during the study period (r=0.49, P=0.03). Glomerular volume did not correlate with HbA(1C), current diabetic glomerulopathy, or ensuing worsening of glomerulopathy. In group 3 every case showed an increase in interstitium (P=0.0009), group 2 showed a decrease (P=0.03), and group 1 showed no change. Increase in interstitial fractional volume correlated with diastolic blood pressure during the study (r=0.54, P=0.01). CONCLUSIONS: In early microalbuminuria, type 1 diabetic patients show glomerular growth, probably compensatory to the developing glomerulopathy. The increase in interstitial volume fraction, demonstrable in early nephropathy, is further augmented over a few years, but is arrested by antihypertensive treatment.

Structural changes in renal arterioles in Type I diabetic patients.

AIMS/HYPOTHESIS: We aimed to obtain data on arteriolar structure in a follow-up study of microalbuminuric diabetic patients. METHODS: Kidney biopsies were obtained at baseline and after 8 years in 18 Type I (insulin-dependent) diabetic patients. Albumin excretion rate, blood pressure and HbA(1C) were measured regularly, and the glomerular filtration rate (GFR) was measured at the time of the kidney biopsy. The biopsy was embedded into plastic blocks and serially sectioned with 1 microm sections. In levels 25 microm apart, afferent and efferent arteriolar profiles were identified and digitised in the electron microscope. The extra-cellular matrix as volume fraction of the media was measured, and estimates of thickness of matrix, media, endothelium and lumen were obtained. Baseline and follow-up biopsies were studied concomitantly. RESULTS: A large increase was seen in matrix volume fraction in afferent ( p = 0.0001) and in efferent arterioles ( p = 0.0004). Estimated thickness of media and matrix increased, whereas endothelial cell thickness decreased, over the 8 years. There was a correlation between the parameters of diabetic glomerulopathy and arteriolar parameters in the biopsies done at 8 years, basement membrane thickness compared with afferent matrix volume fraction: r = 0.74, p = 0.0005. Also aggravation of glomerulopathy and arteriolar structure over 8 years showed positive correlation. Arteriolar parameters correlated with the albumin excretion rate (AER) and inversely with GFR. CONCLUSION/INTERPRETATION: The arteriolar accumulation of matrix parallels that taking place in glomeruli and shows association with functional parameters over 8 years in Type I diabetic patients with microalbuminuria. These changes are considered an important part of the structural lesions in the diabetic kidney underlying the development of diabetic nephropathy.

Impaired contrast sensitivity in adolescents and young type 1 (insulin-dependent) diabetic patients with microalbuminuria.

We compared neurosensorial visual function by psychophysical tests (macular recovery time and contrast sensitivity) in two well matched groups of young Type 1 (insulin-dependent) diabetic patients with micro- and normoalbuminuria, respectively. The patients had normal visual acuity (> or = 1.0) and either no retinopathy or non-proliferative retinopathy. Thirty patients with microalbuminuria (albumin excretion > or = 15 micrograms/min in a least two out of three timed overnight urine samples) were matched (age, diabetes duration, mean one-year HbA1c, gender) with normoalbuminuric (n = 27) patients. Retinopathy (50 degree colour fundus photography) was assessed by counting microaneurysms and hemorrhages as 'red spots'. Contrast sensitivity was examined for the spatial frequencies of 1.5, 3, 6, 12 and 18 cycles per degree (cpd). Macular recovery time (nyctometry) refers to the time-related (2 min) ability of the retina to regain visual acuity following exposure to bright light (photostress). Contrast sensitivity score was reduced in patients with microalbuminuria compared to those without; 18 cpd (mean and 95% confidence intervals): [4.2 (3.8-4.7) vs 5.0 (4.6-5.4), p = 0.03]. Macular recovery performance was not significantly reduced: [21.0 arbitrary units (17.5-24.6) vs 26.0 (22.6-30.7), p = 0.12]. We conclude that impaired contrast sensitivity independent of background retinopathy is shown in a group of young Type 1 (insulin-dependent) diabetic patients with low-grade microalbuminuria compared to a group of patients with normoalbuminuria.