Brain-derived neurotrophic factor is increased in serum and skin levels of patients with chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria is triggered by many direct and indirect aggravating factors including autoreactive/autoimmune mechanisms, infections, non-allergic and pseudoallergic intolerance reactions. However, the role of neuroimmune mechanisms in chronic spontaneous urticaria so far is unclear. OBJECTIVE: Thus, we wanted to address the regulation of the neurotrophin brain-derived neurotrophic factor (BDNF) in serum and inflammatory skin of patients with chronic spontaneous urticaria in comparison to subjects with healthy skin. METHODS: Fifty adult patients with chronic spontaneous urticaria and 23 skin-healthy subjects were studied. Chronic spontaneous urticaria was defined as recurrent weals for more than 6 weeks. Autologous serum skin test was performed in all patients with chronic spontaneous urticaria and BDNF serum levels were analysed by enzyme immunoassay in all subjects. Furthermore, skin biopsies were taken from weals of eight patients with chronic spontaneous urticaria as well as from healthy skin of eight controls to evaluate the expression of BDNF and its receptors including tyrosine kinase (trk) B and pan-neurotrophin receptor p75(NTR) by immunohistochemistry. RESULTS: BDNF serum levels were detectable in all subjects studied. However, BDNF levels were significantly higher in patients with chronic spontaneous urticaria compared to non-atopic skin-healthy controls (P<0.001). Furthermore, epidermal and dermal expression of BDNF and epidermal expression of p75(NTR) was significantly higher in patients with chronic spontaneous urticaria compared with controls (P<0.05-0.001). There was no difference with regard to the expression of trkB between chronic spontaneous urticaria and controls and no difference in BDNF serum levels between autologous serum skin test-positive (n=23) and -negative (n=27) patients with chronic spontaneous urticaria. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that BDNF is increased in serum and diseased skin of patients with chronic spontaneous urticaria, suggesting a role for neurotrophins in the pathophysiology of this chronic inflammatory skin disease. Further studies are needed to address the functional role of BDNF on key target effector cells in chronic spontaneous urticaria to establish new therapeutic implications.

Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial.

AIMS/HYPOTHESIS: The purpose of this study was to evaluate the optimal renoprotective effect of ultrahigh doses of lisinopril, as reflected by short-term changes in urinary albumin excretion rate (UAER), in type 1 diabetic patients with diabetic nephropathy. METHODS: At the Steno Diabetes Center, 49 type 1 diabetic patients with diabetic nephropathy completed this double-masked randomised crossover trial consisting of an initial washout period followed by three treatment periods each lasting 2 months, where all patients received lisinopril 20, 40 and 60 mg once daily in randomised order in addition to slow-release furosemide. Allocation was concealed by sequentially numbered opaque sealed envelopes. UAER, 24 h ambulatory blood pressure (ABP) and estimated GFR were determined at baseline and after each treatment period. RESULTS: All 49 patients completed all three treatment periods. Baseline values were: UAER (geometric mean [95% CI]) 362 (240-545) mg/24 h, 24 h ABP (mean [SD]) 142 (14)/74 (8) mmHg and estimated GFR 75 (29) ml min(-1) 1.73 m(-2). Reductions in UAER from baseline were 63%, 71% and 70%, respectively, with the increasing doses of lisinopril (p < 0.001). Compared with lisinopril 20 mg there was a further reduction in UAER of 23% with lisinopril 40 mg and 19% with 60 mg, p < 0.05. ABP was reduced from baseline by 10/5, 13/7 and 12/7 mmHg (p < 0.001 vs baseline, p < 0.05 for diastolic ABP 20 vs 40 mg, otherwise NS between doses). The difference in UAER between 20 and 40 mg lisinopril was significant after adjustment for changes in ABP (p < 0.01). Two patients were excluded from the study because of an increase in plasma creatinine and one because of high BP; otherwise the study medication was well tolerated with few, mild, dose-independent adverse effects. CONCLUSIONS/INTERPRETATION: Lisinopril 40 mg once daily is generally safe and offers additional reductions in BP and UAER in comparison with the currently recommended dose of 20 mg. Lisinopril 60 mg offers no further beneficial effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT00118976.

Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy.

Reduction of nephrotic range albuminuria is associated with markedly improved renal and cardiovascular outcome in patients with diabetic nephropathy. Aldosterone has been suggested to play a role in the progression of diabetic nephropathy. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on nephrotic range albuminuria and blood pressure in diabetic nephropathy. Twenty Caucasian patients with diabetic nephropathy and nephrotic range albuminuria (>2500 mg/24 h) despite recommended antihypertensive treatment completed this double-masked, randomized crossover trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 2 months, on top of ongoing antihypertensive treatment, including an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker in maximally recommended doses. Median (range) number of antihypertensive drugs was 3 (2-5). After each treatment period, albuminuria, 24-h ambulatory blood pressure, and glomerular filtration rate (GFR) were determined. Spironolactone on top of recommended renoprotective treatment induced a 32% (95% confidence interval (CI): 21-42%) reduction in albuminuria from (geometric mean (95% CI)) 3718 (2910-4749) mg/24 h on placebo treatment (P<0.001). There was a significant reduction in 24-h blood pressure of 6 (2-10)/4 (2-6) mm Hg and day blood pressure of 7 (3-12)/5 (3-7) mm Hg (P<0.01), whereas night blood pressure remained unchanged. Spironolactone induced an insignificant reversible reduction in GFR of 3 ml/min/1.73 m2 from 64 (27) ml/min/1.73 m2. No patients were excluded due to adverse events. Our results suggest that spironolactone treatment on top of recommended renoprotective treatment including maximal renin-angiotensin system blockade may offer additional renoprotection in patients with diabetic nephropathy and nephrotic range albuminuria.

Anaemia in diabetes: Is there a rationale to TREAT?

BACKGROUND: Anaemia is a common finding in patients with diabetes, particularly in those with overt nephropathy or renal impairment. In tertiary clinics, at least one outpatient in five with diabetes has anaemia, for whom it constitutes a significant additional burden. DISCUSSION: Anaemia is associated with an increased risk of diabetic complications including nephropathy, retinopathy and macrovascular disease. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in diabetes. While several factors contribute to the increased prevalence of anaemia in diabetes, the failure of the kidney to increase erythropoietin in response to falling haemoglobin appears to be the dominant factor. Although there is a clear rationale for correcting anaemia in people with diabetes, it remains to be established whether this will lead to improved outcomes. Moreover, the balance of risks, costs, and benefits remains to be established in patients with diabetes. The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alpha) Therapy (TREAT) is a randomised controlled trial designed to determine the impact of anaemia correction on mortality and non-fatal cardiovascular events in patients with type 2 diabetes and stage 3-4 nephropathy. CONCLUSION: It is anticipated that TREAT will help to define the optimal approach to the management of anaemia in diabetes.

Remission of nephrotic-range albuminuria reduces risk of end-stage renal disease and improves survival in type 2 diabetic patients.

AIMS/HYPOTHESIS: We evaluated the impact of remission of nephrotic-range albuminuria (>2500 mg/24 h) (NRA) on end-stage renal disease (ESRD) and mortality in type 2 diabetic patients with nephropathy. METHODS: This was a follow-up observational study involving all 79 patients (35%; 62 men, 17 women) with NRA from a cohort of type 2 diabetic patients with nephropathy that was followed for at least 3 years at the Steno Diabetes Center (n=227). Patients were followed from the onset of NRA until death or January 2005. The mean age (+/-SD) was 60+/-8 years and known diabetes duration was 14+/-7 years. Remission of NRA was defined as sustained albuminuria <600 mg/24 h for at least 1 year. RESULTS: The duration of follow-up after onset of NRA was 6.5 years (range 2-20 years). Remission was induced in 20 (25%) of the patients, all treated with ACE inhibitors or angiotensin-II receptor blockers. Remission lasted 4.1 years (range 1-10 years) and only three patients relapsed. At the end of follow-up, only 30% (two ESRD and four deaths) of the 20 patients with remission had reached the composite endpoint of ESRD or death, in contrast to 66% (16 ESRD and 23 deaths) of the 59 patients without remission (p<0.01). Cox regression analysis revealed that remission was associated with a risk reduction of 67% (95% CI 10-87) for reaching the composite endpoint of ESRD or death and of 69% (95% CI 21-88%) for death alone. Male sex, greater age and systolic blood pressure at onset of NRA were also independently associated with an increased risk of ESRD and death. CONCLUSIONS/INTERPRETATION: Aggressive antihypertensive treatment can lead to long-term remission of NRA in a sizeable proportion of patients with type 2 diabetes. Such remission is associated with a slower progression of nephropathy and substantially improved survival.

Dual blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy: the role of aldosterone.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with both ACE inhibitors and angiotensin II receptor-blockers has been shown to reduce both albuminuria and blood pressure compared to either monotherapy. The mechanisms behind these beneficial effects are not known, and we hypothesized that the effect of dual RAAS blockade may be due to a more complete suppression of circulating aldosterone. We performed a combined analysis on three randomized, double-masked, cross-over trials where 51 type 1 diabetic patients suffering from diabetic nephropathy received 8 weeks of dual RAAS blockade using an angiotensin II receptor blocker in combination with an ACE inhibitor and 8 weeks of monotherapy with the same ACE inhibitor. Albuminuria, 24 h blood pressure, GFR, and plasma aldosterone were determined at the end of each treatment period. Compared to ACE inhibition alone, dual RAAS blockade lowered blood pressure by 7/5 mm Hg from 137/76 mm Hg, decreased albuminuria by 37% from 558 mg/24 hour, and reduced plasma aldosterone by 28% from 59 pg/ml and caused a reversible decline in GFR of 4 ml/min/1.73 m2 (p < or = 0.01 for all comparisons). There was and a significant correlation between changes in 24-hour diastolic blood pressure and changes in albuminuria. Furthermore, the antialbuminuric response to dual blockade was influenced by the ACE/ID polymorphism, that is, patients carrying the D-allele had a significantly lower reduction of 31% compared to the 55% in patients with the II genotype (p = 0.021). Multiple linear regression analysis revealed that ACE/ID genotypes and reduction in plasma aldosterone, diastolic blood pressure and GFR is associated with changes in albuminuria on dual blockade treatment (R2 (adjusted) = 0.57, p < 0.001). Dual RAAS blockade is a new treatment concept that may offer additional cardiovascular and renal protection in type 1 diabetic patients with diabetic nephropathy. The beneficial response may be influenced by genetic factors and reductions in blood pressure and plasma aldosterone concentrations.

Effect of short-term hyperglycaemia on haemodynamics in type 1 diabetic patients.

OBJECTIVES: Mechanisms underlying glucose-mediated development and progression of diabetic complications are incompletely understood. We tested the impact of short-term hyperglycaemia on systemic blood pressure and regulatory hormones in type 1 diabetic patients. DESIGN AND METHODS: We included 18 patients [13 men, mean (SEM) diabetes duration 10 (1) years] without signs of autonomic neuropathy or renal complications in a randomized single-blinded cross-over trial using insulin-glucose clamp technique. Patients were clamped for 90 min to blood glucose of 5 mmol L(-1) (euglycaemia) and 15 mmol L(-1) (hyperglycaemia) in random order. Blood pressure was measured noninvasively every 5 min (Takeda TM2421 device). Regulatory hormones were determined at the end of each clamp period. RESULTS: Systolic blood pressure increased [mean (95% CI)] 3 (1, 5) mmHg during hyperglycaemia from 123 (SEM 2) during euglycaemia, P=0.01. Diastolic blood pressure remained unchanged at 78 (2) mmHg. Hyperglycaemia reduced plasma concentrations of: renin [14 (4, 23)%, P=0.02], angiotensin II [17 (8, 25)%, P<0.01] and adrenaline [20 (10, 29)%, P<0.01]. Plasma concentration of atrial natriuretic peptide increased by 11 (6, 17) pg mL(-1) (P<0.01) from 43 (2) pg mL(-1). We calculated a median (range) increase in extracellular volume and plasma volume (PV) of 2.6 (0.7-5.3)% and 5.0 (-4.7 to 8.6)%, respectively. CONCLUSIONS: In type 1 diabetic patients without signs of autonomic neuropathy short-term hyperglycaemia induced a modest increase in systolic blood pressure and suppression of the renin-angiotensin system, possibly caused by PV expansion because of fluid shift from intra- to extracellular compartment.

Pregnancy and progression of diabetic nephropathy.

AIMS/HYPOTHESIS: Pregnancy could damage kidney function in diabetic nephropathy. We investigated the long-term impact of pregnancy on the progression of diabetic nephropathy. METHODS: Our observational follow-up study included all women patients with Type I (insulin-dependent) diabetes mellitus who developed diabetic nephropathy between 1970 and 1989 at Steno Diabetes Center (n = 93). Follow-up lasted 16 years (range 3-28) from the onset of diabetic nephropathy until death or the year 2000. A total of 26 women became pregnant after the onset of diabetic nephropathy (group A). The remaining 67 served as control subjects (group B). All patients received aggressive antihypertensive treatment (blood pressure goal < 140/90 mmHg). RESULTS: The two groups were comparable at onset of diabetic nephropathy regarding blood pressure, albuminuria, s-cholesterol, smoking, retinopathy and s-creatinine (mean 79(SD 23) micromol/l). The slopes of 1/s-creatinine (1000.l.micromol(-1).year(-1)) during the whole observation period were -0.39(0.40) compared with -0.41(0.70) (group A vs B-NS). The slopes of 1/s-creatinine before and after pregnancy were similar. Decline in creatinine clearance (ml/min/yr) was 3.2 (3.4) compared with 3.2 (5.1) (group A vs B -NS). At the end of follow-up, 35 % (95 %-CI:17-53) of the pregnant women had died and 19 % (7-39) had reached end stage renal disease compared to 34 % (23-45) and 24 %(14-34) of the control subjects, respectively(NS). Group A and B had similar blood pressure levels during the whole observation period: 136(13)/83(7) vs 139 (14)/85(7) mmHg (NS). CONCLUSION/INTERPRETATION: Pregnancy has no adverse long-term impact on kidney function and survival in Type I diabetic patients with well-preserved kidney function (normal serum creatinine) suffering from diabetic nephropathy.

Evolving strategies for renoprotection: diabetic nephropathy.

A cumulative incidence of diabetic nephropathy of 25-40% has been documented after duration of diabetes of at least 25 years in both type 1 and type 2 diabetic patients. Diabetic nephropathy has become the leading cause (25-44%) of end-stage renal failure in Europe, the United States and Japan. Until the early 1980s, no renoprotective treatment was available for use in diabetic nephropathy. Death occurred on average 5-7 years after the onset of persistent proteinuria. It should be recalled that development of treatment modalities occurred in reverse order: in the early 1980s, antihypertensive treatment of diabetic nephropathy was introduced, and in the early 1990s, primary and secondary prevention with improved glycaemic control and angiotensin-converting enzyme inhibition. The two main treatment strategies for primary prevention of diabetic nephropathy are improved glycaemic control and blood pressure lowering, particularly using drugs such as angiotensin-converting enzyme inhibitors. Megatrials and meta-analyses have clearly demonstrated the beneficial effect of both the above-mentioned treatment modalities. Secondary prevention, that is, treatment modalities applied to diabetic patients with high risk of development of diabetic nephropathy (e.g. those with microalbuminuria) has been documented, applying angiotensin-converting enzyme inhibitors in both type 1 and type 2 diabetic patients. Furthermore, improved metabolic control reduces the risk of progression. In special cases (such as pancreas transplantation) even reversal of diabetic glomerular lesions has been documented. Antihypertensive treatment of patients with overt nephropathy induces a reduction in albuminuria, a reduction in the rate of decline of glomerular filtration rate, delays development of end-stage renal failure and improves survival. Many potential treatment modalities in preventing and treating diabetic nephropathy are presently being evaluated.

Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with Type 1 diabetes mellitus with microalbuminuria and overt nephropathy.

AIMS: Elevated urinary albumin excretion is associated with macrovascular atherosclerotic complications in Type 1 diabetes mellitus. Adhesion molecules mediate leucocyte adhesion to the endothelium early in the atherosclerotic process. The present study tests the hypothesis that microalbuminuria and diabetic nephropathy are associated with elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1, soluble intercellular adhesion molecule (sICAM)-1, and soluble E-selectin (sE-selectin) aiming to illustrate factors of potential pathogenetic relevance for the excess cardiovascular disease in diabetic patients with renal complications. METHODS: Soluble adhesion molecule concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in healthy controls (n = 16) and in 59 Type 1 diabetic patients: group 1-patients with normoalbuminuria (n = 16); group 2-patients with microalbuminuria (n = 15); group 3-patients with macroalbuminuria and normal serum creatinine (n = 15), group 4-patients with macroalbuminuria and moderately elevated serum creatinine (n = 13). RESULTS: Plasma concentrations of sVCAM-1 and sICAM-1 were similar in healthy controls and normoalbuminuric Type 1 diabetic patients, but the concentrations were increased by the presence of microalbuminuria and overt nephropathy (P < 0.001 and P < 0.0001, ANOVA). Concentrations of sE-selectin did not differ between diabetic patients and controls. CONCLUSIONS: Plasma concentration of sICAM-1 is elevated in Type 1 diabetic patients with microalbuminuria and the concentrations of sICAM-1 as well as sVCAM-1 are elevated in patients with macroalbuminuria and normal s-creatinine. The elevated plasma concentrations of these soluble adhesion molecule concentrations in patients with renal complication can be of pathogenetic importance for the development of atherosclerosis and plasma soluble adhesion molecule concentrations may provide additional information on cardiovascular risk.

Progression of diabetic nephropathy in normotensive type 1 diabetic patients.

BACKGROUND: The first aim of our long-term study was to describe the natural history of diabetic nephropathy in 59 normotensive type 1 diabetic patients. Secondly, we evaluated genetic and nongenetic progression promoters. METHODS: The following progression promoters were determined: the insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene, blood pressure, albuminuria, hemoglobin A1c, cholesterol, smoking, height, and gender. We studied the natural history by measuring 51Cr-EDTA plasma clearance at yearly intervals at least three times during [median (range)] 5.5 (2.2 to 18.3) years. RESULTS: At baseline the three groups (II, N = 11; ID, N = 25, and DD, N = 23) had comparable GFR (103 +/- 16; 99 +/- 19; 113 +/- 22 ml/min/1.73 m2, respectively; mean +/- SD), arterial blood pressure, albuminuria, and hemoglobin A1c. During the follow-up there was a median rate of decline in GFR in all 59 patients of 1.2 (range 12.9 to -4.4) ml/min/year. During the study period no significant differences were observed in: the rate of decline in glomerular filtration rate [median (range) 0.9 (10.6 to -1.9); 2.5 (12.9 to -4.4); 1.4 (10.8 to -1.9 ml/min/year)], arterial blood pressure, albuminuria, hemoglobin A1c or cholesterol between the three groups (II, ID and DD), respectively. At baseline, multiple linear regression analysis including the above-mentioned putative risk factors revealed that albuminuria, short stature, and male gender independently predict an enhanced decline in GFR [R2 (adjusted) = 0.33; P < 0.002]. During the follow-up period, only albuminuria acted as an independent progression promoter [R2 (adjusted) = 0.37; P < 0.0001]. CONCLUSIONS: Our study revealed a rather slow progression of kidney disease in normotensive type 1 diabetic patients with diabetic nephropathy. Albuminuria, short stature, and male gender act as progression promoters in such patients.

Improved visual function in IDDM patients with unchanged cumulative incidence of sight-threatening diabetic retinopathy.

OBJECTIVE: To evaluate trends in visual acuity and the cumulative incidence of diabetic retinopathy in a clinic-based observational follow-up study. RESEARCH DESIGN AND METHODS: All patients visiting Hvidore Hospital in 1984 whose diagnosis of IDDM had been made before 41 years of age and between 1965 and 1979 (n = 356) were followed until 1994 or until their deaths. All patients were Caucasians and resided in Copenhagen. Patients were divided into three prevalence cohorts based on time of diabetes onset: group A, 1965-1969 (n = 113); group B, 1970-1974 (n = 130); and group C, 1975-1979 (n = 113). RESULTS: Fifteen years after diabetes onset, the visual acuity was significantly improved in patients with increasing calendar year of the disease onset. The median (interquartile range) visual acuity was 1.0 (0.8-1.0), 1.0(0.9-1.0), and 1.0 (1.0-1.0) in groups A, B, and C, respectively (P < 0.01 overall; P = 0.28 for group A vs. group B; and P < 0.01 for group A vs. group C) with 60, 66, and 93 having a visual acuity of 1.0 in groups A, B, and C, respectively. The cumulative incidence (+/-SEM), expressed as a percentage and calculated according to the life-table method, of proliferative retinopathy, maculopathy, and laser-treated retinopathy 15 years after onset of diabetes were, respectively, 13+/-3, 11+/-3, and 12+/-3 in group A; 16+/-3, 12+/-3, and 21+/-4 in group B; 11+/-3, 5+/-2, and 12+/-3 in group C, respectively (NS). The development of proliferative retinopathy was associated with the degree of retinopathy and albuminuria at baseline and the mean HbA1c during follow-up. CONCLUSIONS: The study revealed an improvement in visual acuity with increasing calendar year of diabetes onset but an unchanged cumulative incidence of diabetic retinopathy.

Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy.

The antiproteinuric effect of angiotensin converting enzyme (ACE) inhibition in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy varies considerably. Therefore, we tested the potential role of an insertion (I)/deletion (D) polymorphism of the ACE gene on this early antiproteinuric responsiveness in an observational follow-up study. Sixty (II, N = 13; ID, N = 26 and DD, N = 21) young hypertensive IDDM patients suffering from diabetic nephropathy were investigated during three months before and for the initial six month period during ACE inhibition [captopril 44 (SD 22) mg/24 hr, no differences in drug dose between groups]. Blood pressure (MABP) and albuminuria (ELISA) were measured three (1 to 6) times before and three (1 to 13) times during ACE inhibition. At baseline the groups (II/ID/DD) had comparable (1) mean arterial blood pressure (MABP mm Hg) of 113 +/- 10/108 +/- 9/114 +/- 8, (2) albuminuria (geometric mean with 95% CI) 1394 (747 to 2608)/1176 (844 to 1797) and 1261 (827 to 2017) mg/24 hr, and (3) serum creatinine (geometric mean with 95% CI), 80 (68 to 93)/85 (76 to 97)/103 (85 to 119) mumol/liter, respectively. Angiotensin converting enzyme inhibition induced a significant reduction in MABP, albuminuria and kidney function in all three groups (II/ID/DD; P < 0.05): (1) MABP (mean +/- SD) 12 +/- 7/5 +/- 7/8 +/- 9 mm Hg (ANOVA, P = 0.02); (2) albuminuria [mean (95% CI)] 61 (34 to 77)/22 (3 to 37)/31 (13 to 46) %, (ANOVA, P < 0.01); and (3) increasing serum creatinine [mean (95% CI)] 8 (4 to 12)/9 (3 to 16)/8 (0 to 16) % (ANOVA, NS), respectively. Adjusting for differences in reduction in MABP did not change the association between decrease in albuminuria and ACE/ID genotypes (P < 0.01). A multiple linear regression analysis revealed that the ACE/ID polymorphism, albuminuria and MABP at baseline independently influenced the decline in albuminuria after initiation of ACE inhibition (R2 = 0.21, P < 0.01). A significant association between changes in MABP and albuminuria was demonstrated (R2 = 0.16, P < 0.01). Our data show that hypertensive albuminuric IDDM patients with the II genotype are particularly susceptible to commonly advocated renoprotective treatment.

Microalbuminuria as an early indicator of osteopenia in male insulin-dependent diabetic patients.

Reduced bone mineral density (BMD), termed diabetic osteopenia, has been reported in patients with insulin-dependent (Type 1) diabetes mellitus (IDDM). To examine BMD in long-term IDDM patients with normal kidney function, but with different degrees of urinary albumin excretion rate (UAER), compared to that of patients with elevated plasma creatinine, 36 IDDM male patients (mean duration 27 years) were subdivided according to UAER (<30, 30-300, >300, >300 mg 24 h(-1) and plasma creatinine 0.120-0.350 mmol l(-1)) and 15 controls were recruited. BMD was measured by dual energy X-ray absorptiometry and UAER by enzyme linked immunosorbent assay. BMD was normal in IDDM patients with normal UAER and reduced in the femoral neck, the trochanter major, and the Wards triangle in patients with increased UAER (p < 0.01, p < 0.05, p < 0.02). BMD correlated to creatinine clearance in both cortical and cancellous bone sites (p < 0.001, p < 0.0001), and inversely to the levels of plasma PTH (p < 0.0005). We conclude that BMD is normal in long-term IDDM male patients with normal kidney function and normal UAER and reduced in patients with increased UAER. Diabetic osteopenia seems to be a progressive phenomenon related to diabetic nephropathy and associated with the decrease in creatinine clearance and with the resulting rise in plasma PTH.

[Diabetic nephropathy. Unchanged occurrence in patients with insulin-dependent diabetes mellitus]. / Diabetisk nefropati. Uaendret forekomst hos patienter med insulinkraevende diabetes mellitus.

Recently, a dramatic decline in the cumulative incidence of diabetic nephropathy (less than 10% after 25 years of diabetes) has been reported in IDDM patients diagnosed between 1961 and 1980. In a clinic based study we assessed recent trends in the incidence of diabetic nephropathy. All 356 patients in whom IDDM was diagnosed before the age of 41 years between 1965 and 1979, identified in 1984 were followed to 1991 or to death. The cumulative incidence of diabetic nephropathy (urinary albumin excretion 300 mg/24 hours in two out of three consecutive samples) after 15 years of diabetes and in 1991 were (cumulative incidence (SE)): 18 (4)% and 35 (5)% (onset of diabetes 1965-69, n = 113), 20 (4)% and 35 (5)% (onset of diabetes 1970-74, n = 130), and 16 (5)% (onset of diabetes 1975-79, n = 113), respectively (ns). The mean (SE) haemoglobin A1c measured yearly beginning in 1984 was higher in patients with nephropathy (9.4 (0.1)%), and persistent microalbuminuria (8.9 (0.1)%) than in patients with normoalbuminuria (8.5 (0.1)%, (p < 0.001)). Our study revealed no decline in the cumulative incidence of diabetic nephropathy with increasing calendar year of diabetes onset. This may in part be explained by poor metabolic control and a high prevalence of smokers (58-71%).

The acute effect of smoking on systemic haemodynamics, kidney and endothelial functions in insulin-dependent diabetic patients with microalbuminuria.

The acute effect of smoking upon arterial blood pressure, urinary albumin excretion rate, glomerular filtration rate and transcapillary escape rate of albumin were investigated in nine normotensive insulin-dependent diabetic patients with microalbuminuria, who had been smoking for 19 (range 4-30) years. In a prospective, open randomized cross-over design, patients were investigated with and without smoking three cigarettes per hour during a 5.5-h period. A rise in systolic blood pressure and heart rate (Takeda TM2420, median (range)) was observed during the smoking day (10(-11 to 14) mmHg and 8 (-1 to 19) beats min-1), compared to the non-smoking day (1 mmHg (-7 to 13) (p = 0.05) and 0 beats min-1 (-2 to 4) (p < 0.01)). Urinary albumin excretion rate (ELISA), glomerular filtration rate (plasma clearance of 51Cr-EDTA) and transcapillary escape rate of albumin (125I-albumin) remained the same with or without smoking. Our study suggests that heavy smoking induces an abrupt rise in systolic blood pressure and heart rate, while vascular leakage of albumin and glomerular filtration rate remain unaltered in normotensive insulin-dependent diabetic patients with microalbuminuria who had been smoking for several years.

Benefits of long-term antihypertensive treatment on prognosis in diabetic nephropathy.

We assessed the prognosis of diabetic nephropathy during long-term antihypertensive treatment as compared to the prognosis during the natural history of this complication in a prospective study of all IDDM patients (N = 45) aged under 50 with onset of diabetes before the age of 31 who developed diabetic nephropathy between 1974 and 1978 at Steno Diabetes Center, and were followed until death or for at least 16 years [median 16 (4 to 21) years]. Antihypertensive treatment was started 3 (0 to 13) years after onset of diabetic nephropathy. Mean arterial blood pressure at start of antihypertensive treatment was 148/96 (sd 12/10) mm Hg and 143/86 (16/6) mm Hg during the whole interval of antihypertensive treatment (P < 0.01). The cumulative death rate was 45% (95% C.I. 38 to 52) 16 years after onset of diabetic nephropathy, in contrast to previous reports 88% and 94% 12 and 16 years after onset of diabetic nephropathy, respectively. The median survival time in our study exceeded 16 years as compared to five and seven years in untreated patients in the past. Uremia was the main cause of death (12 patients; 55%). In 1994 serum creatinine was 116 (74 to 311) mumol/liter in the 23 surviving patients. The preservation of kidney function and the prognosis of diabetic nephropathy has improved during the past two decades mainly because of effective antihypertensive treatment.

Unchanged incidence of diabetic nephropathy in IDDM patients.

Recently, a dramatic decline in the cumulative incidence of diabetic nephropathy (< 10% after 25 years of diabetes) has been reported in insulin-dependent diabetes mellitus (IDDM) patients diagnosed before the age of 15 years between 1961 and 1980. In a clinic-based study, we assessed recent trends in the incidence of diabetic nephropathy. All 356 patients in whom IDDM was diagnosed before the age of 41 years between 1965 and 1979, identified in 1984, were followed until 1991 or until death. All patients were Caucasians and resided in Copenhagen. The cumulative incidences (life-table method) of diabetic nephropathy (urinary albumin excretion > or = 300 mg/24 h in two out of three consecutive samples) after 15 years of diabetes and in 1991 were 18 +/- 4 and 35 +/- 5% (cumulative incidence +/- SE; onset of diabetes 1965-1969, n = 113), 20 +/- 4 and 35 +/- 5% (onset of diabetes 1970-1974, n = 130), and 16 +/- 5% (onset of diabetes 1975-1979, n = 113), respectively (NS at 15 years). The prevalence of persistent microalbuminuria (31-299 mg/24 h) at time of follow-up was 24% (95% confidence interval: 16-33) in the group with onset of diabetes in 1965-1969, 28% (20-36) with onset of diabetes in 1970-1974, and 19% (13-28) with onset of diabetes in 1975-1979 (NS). The mean +/- SE HbA1c measured yearly beginning in 1984 was higher in patients with nephropathy (9.4 +/- 0.1%) and persistent microalbuminuria (8.9 +/- 0.1%) than in patients with normoalbuminuria (8.5 +/- 0.1%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)