Mari-Anne Gall

Albuminuria and Poor Glycemic Control Predict Mortality in NIDDM

The impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 Caucasian patients with non-insulin-dependent diabetes mellitus (NIDDM) followed for 5 years. One hundred ninety-one (109 men and 82 women) patients with normoalbuminuria (albumin excretion rate [AER] <30 mg/24 h), 86 (50 men and 36 women) patients with microalbuminuria (AER 30–299 mg/24 h), and 51 (43 men and 8 women) patients with macroalbuminuria (AER ≥300 mg/24 h) <66 years old at entry were followed from 1987 until death or until 1 January 1993. Mean age at entry was 54 (SD 9) years. In January 1993, 8% of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria had died (predominantly from cardiovascular disease) (P <0.01 [normoalbuminuria versus micro- and macroalbuminuria] and P <0.05 [microalbuminuria versus macroalbuminuria]). Cox multiple regression analysis revealed significant predictors of all-cause mortality to be preexisting coronary heart disease (relative risk [95% confidence interval]), 2.9 (1.6–5.1); log10AER (factor 10), 1.9 (1.4–2.6); HbA1c level (%), 1.2 (1.0–1.4); and age (years), 1.08 (1.03–1.13). Significant predictors of cardiovascular mortality included preexisting coronary heart disease, 6.1 (2.8–13.5); macroalbuminuria, 2.5 (1.1–5.8); HbA1c level (%), 1.3 (1.1–1.6); and systolic blood pressure (10 mmHg), 1.2 (1.0–1.4). Univariate Cox survival analysis in the normoalbuminuric group revealed that AER above the median of 8 mg/24 h was associated with an increased all-cause mortality risk of 2.7 (0.93–7.69) (P = 0.07). We conclude that abnormally elevated urinary albumin excretion and poor glycemic control indicate a substantially increased allcause, mainly cardiovascular, mortality risk in NIDDM patients.

Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus : prospective, observational study

Abstract Objective: To evaluate putative risk factors for the development of incipient diabetic nephropathy (persistent microalbuminuria) and overt diabetic nephropathy (persistent macroalbuminuria) in patients with non-insulin dependent diabetes. Design: Prospective, observational study of a cohort of white, non-insulin dependent diabetic patients followed for a median period of 5.8 years. Setting: Outpatient clinic in tertiary referral centre. Subjects: 191 patients aged under 66 years with non-insulin dependent diabetes and normoalbuminuria (urinary albumin excretion rate<30 mg/24 h) who attended the clinic during 1987. Main outcome measures: Incipient and overt diabetic nephropathy. Results: Fifteen patients were lost to follow up. Thirty six of the 176 remaining developed persistent microalbuminuria (30-299 mg/24 h in two out of three consecutive 24 hour urine collections) and five developed persistent macroalbuminuria (≥300 mg/24 h in two out of three consecutive collections) during follow up. The five year cumulative incidence of incipient diabetic nephropathy was 23% (95% confidence interval 17% to 30%). Coxs multiple stepwise regression analysis revealed the following risk factors for the development of incipient or overt diabetic nephropathy: increased baseline log urinary albumin excretion rate (relative risk 11.1 (3.4 to 35.9); P<0.0001); male sex (2.6 (1.2 to 5.4); P<0.02); presence of retinopathy (2.4 (1.3 to 4.7); P<0.01); increased serum cholesterol concentration (1.4 (1.1 to 1.7); P<0.01); haemoglobin A 1c concentration (1.2 (1.0 to 1.4); P<0.05); and age (1.07 (1.02 to 1.12); P<0.01). Known duration of diabetes, body mass index, arterial blood pressure, serum creatinine concentration, pre-existing coronary heart disease, and history of smoking were not risk factors. Conclusion: Several potentially modifiable risk factors predict the development of incipient and overt diabetic nephropathy in normoalbuminuric patients with non-insulin dependent diabetes.

Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type 2 (non-insulin-dependent) diabetic patients.

SummaryThe prevalence of micro- and macroalbuminuria was determined in Type 2 (non-insulin-dependent) diabetic patients, less than 76 years of age, attending a diabetic clinic during 1987. All eligible patients (n=557) were asked to collect a 24-h urine sample for quantitative albumin analysis. Urine collections were obtained in 296 males and 253 females (96%). Normoalbuminuria were defined as urinary albumin excretion≤30 mg/24 h (n=323), microalbuminuria as 31–299 mg/24 h (n=151), and macroalbuminuria as ≥300 mg/ 24 h (n=75). The prevalence of macroalbuminuria was significantly higher in males (20%) than in females (6%), while the prevalence of microalbuminuria was almost identical in males (26%) and females (29%). The prevalence of arterial hypertension increased with increased albuminuria, being 48%, 68%, and 85% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of proliferative retinopathy rose with increasing albuminuria, being 2%, 5% and 12% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of coronary heart disease, based on Minnesota coded electrocardiograms, was more frequent in patients with macroalbuminuria (46%) compared to patients with microalbuminuria (26%) and patients with normoalbuminuria (22%). Foot ulcers were more frequent in micro- and macroalbuminuric patients, being 13% and 25%, respectively, compared to 5% in patients with normoalbuminuria. This cross-sectional study has revealed a high prevalence of microalbuminuria (27%) and macroalbuminuria (14%) in Type 2 diabetic patients. Patients with raised urinary albumin excretion are characterized by obesity, elevated haemoglobin Alc, increased frequency of arterial hypertension, proliferative retinopathy, coronary heart disease and foot ulcers. Thus, these findings suggest that urinary excretion of albumin should be monitored routinely in patients with Type 2 diabetes.

Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy.

The aim of our study was to evaluate whether inhibition of ACE (lisinopril 10–20 mg/day) can reduce the rate of decline in kidney function more than reducing blood pressure with conventional antihypertensive treatment (atenolol 50–100 mg/day), usually in combination with a diuretic. We performed a prospective, randomized, parallel study for 42 months, double blind for the first 12 months and single blind thereafter. Forty-three (21 lisinopril and 22 atenolol) hypertensive NIDDM patients with diabetic nephropathy were enrolled. Data from 36 patients (17 lisinopril and 19 atenolol, 60 ± 7 years of age, 27 men) who completed at least 12 months of the study period are presented. At baseline, the two groups were comparable: glomerular filtration rate (51Cr-EDTA plasma clearance) was 75 ± 6 and 74 ± 8 ml · min−1 · 1.73 m−2, mean 24-h ambulatory blood pressure (A&D TM2420) was 110 ± 3 and 114 ± 2 mmHg, and 24-h urinary albumin excretion rate was 961 (range 331–5,727) and 1,578 (476–5,806) mg/24 h in the lisinopril and atenolol groups, respectively. The mean follow-up time was similar, 37 and 35 months in the lisinopril and atenolol groups, respectively. Mean ambulatory blood pressure was equally reduced in the two groups, 12 ± 2 and 10 ± 2 mmHg in the lisinopril and atenolol groups, respectively. Glomerular filtration rate declined in a biphasic manner with a faster initial (0 to 6 months) change of 1.25 ± 0.49 and 0.81 ± 0.29 ml · min−1 · month−1 followed by a slower sustained decline (6 to 42 months) of 0.59 ± 0.10 and 0.54 ± 0.13 ml · min−1 · month−1 in the lisinopril and atenolol groups, respectively. No significant differences were observed in either initial or sustained decline in glomerular filtration rate between the two groups. Urinary albumin excretion was reduced (% reduction of baseline) more in the lisinopril than in the atenolol group, at 55 (95% CI 29–72) and 15% (−13 to 34), respectively (P = 0.01). In conclusion, the relentless decline in kidney function characteristically found in hypertensive NIDDM patients with diabetic nephropathy can be reduced equally effectively by two antihypertensive treatments, the β-blocker atenolol and the ACE inhibitor lisinopril.

Prevalence of Arterial Hypertension in Diabetic Patients Before and After the JNC-V

OBJECTIVE To compare the prevalence of arterial hypertension in patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) according to blood pressure (BP) criteria from the World Health Organization (WHO) and The Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V). RESEARCH DESIGN AND METHODS Two cohorts of Caucasian patients attending the outpatient clinic at Hvidöre Hospital were identified: 1) 957 patients with IDDM; 53% men, 40 (18–75) years of age (mean [range]); and 2) 549 patients with NIDDM; 53% men, 60 (20–76) years of age. BP was measured at least yearly, while patients rested in a sitting position, with a standard clinical sphygmomanometer. Patients were classified as hyper- or normotensive based on average BP during a 3-year follow-up period. Patients receiving antihypertensive treatment were classified as hypertensives. RESULTS In IDDM patients, the prevalence of arterial hypertension rose from 15 to 42% in the normoalbuminuric group, from 26 to 52% in the microalbuminuric group, and from 61 to 79% in the macroalbuminuric group when WHO and JNC-V criteria were compared. The corresponding rises in NIDDM patients were from 51 to 71% (normo-), from 73 to 90% (micro-), and from 82 to 93% (macroalbuminuria). Of the untreated hypertensive patients, 78% of IDDM patients and 50% of NIDDM patients had stage 1 (140–159/90–99 mmHg) hypertension; 20% of IDDM patients and 37% of NIDDM patients had stage 2 (160–179/100–109 mmHg) hypertension. Two out of three untreated hypertensive patients had isolated systolic hypertension. CONCLUSIONS The new JNC-V criteria approved by the American Diabetes Association leads to a considerable increase in the prevalence of arterial hypertension in a population of IDDM and NIDDM patients. Isolated systolic hypertension contributes importantly.

Glomerular structure and function in proteinuric Type 2 (non-insulin-dependent) diabetic patients

SummaryGlomerular ultrastructure was examined in a series of 20 Type 2 (non-insulin-dependent) diabetic patients with proteinuria. Reference was made to data previously obtained in non-diabetic kidney donors and in Type 1 (insulindependent) diabetic patients with similar degrees of proteinuria. The Type 2 diabetic patients demonstrated the changes which characterize the diabetic glomerulopathy seen in Type 1 diabetic patients: basement membrane thickening, and increase in the mesangium and mesangial matrix expressed as fraction of the glomerular volume. Among the Type 2 diabetic patients there was more variation then among the Type 1 diabetic patients, as this group included subjects with normal parameters. The group means and coefficients of variation (=SD/mean) of the glomerulopathy parameters combined in the glomerulopathy index=basement membrane thickness/10+Vv(matrix/glom)·100 were 81 (0.30) and 92 (0.15) in the two diabetic groups, clearly different from the non-diabetic index, 42 (0.16). All Type 2 diabetic patients who also had retinopathy had a glomerulopathy index above the normal range. Similar changes in glomerular composition were seen in the two diabetic groups: with increasing glomerulopathy the volume of matrix dominated over the peripheral basement membrane, and a shift in the ratio of interfaces was seen: mesangial surface towards capillary lumen increased relative to the urinary surface, and peripheral capillary surface comprised less of the total capillary surface. Data indicated marked glomerular hypertrophy, which correlated with the mesangial volume fraction, thus encompassing preserved filtration surface per glomerulus. An inverse correlation obtained between the index of glomerulopathy and current glomerular filtration rate, as well as the ensuing rate of decline in glomerular filtration rate, as well as the ensuing rate of decline in glomerular filtration rate: (index (glomerulopathy) vs rate of decline in glomerular filtration rater=0.84,p<0.0001). No correlation was found between glomerular volume and the ensuing rate of decline in glomerular filtration rate.

The course of kidney function in type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy.

SummaryWe evaluated the impact of some putative progression promoters on kidney function in albuminuric Type 2 (non-insulin-dependent) diabetic patients with biopsyproven diabetic glomerulosclerosis. Twenty-six patients (1 female) with a mean age of 52 (standard error 2) years and a known mean duration of diabetes of 9 (1) years were followed-up prospectively for a mean of 5.2 (range 1.0–7.0) years. Twenty-one patients received antihypertensive treatment. During the observation period the glomerular filtration rate decreased from 83 (24–146) to 58 (2–145) ml·min−1·1.73 m−2 (mean (range)) (p<0.001). The mean rate of decline in glomerular filtration rate was 5.7 (−3.5 to 22.0) ml/min per year. Albuminuria increased from 1.2 (0.3–7.2) to 2.3 (0.4–8.0) g/24 h (geometric mean (range)) (p<0.001). Arterial blood pressure remained unchanged: 162/93 (SE 4/3) and 161/89 (4/2) mm Hg. Univariate analysis showed the rate of decline in glomerular filtration rate to correlate with systolic blood pressure (r=0.71,p<0.001), mean blood pressure (r=0.56,p<0.005), albuminuria (r=0.58,p<0.005) and the initial glomerular filtration rate (r=−0.49,p<0.02). The rate of decline in glomerular filtration rate did not correlate significantly with dietary protein intake, total cholesterol, high-density lipoprotein cholesterol or HbA1c. Three patients died from uraemia and four patients died from cardiovascular disease. Two patients required renal replacement therapy at the end of the observation period. Our prospective observational study revealed that one-fifth of the patients developed end-stage renal failure during the 5-year observation period. The decline in glomerular filtration rate varied considerably between patients. Increase in arterial blood pressure to a hypertensive level is an early feature of diabetic nephropathy. Elevated systolic blood pressure accelerates the progression of diabetic nephropathy in Type 2 diabetic patients.

Effective Antihypertensive Treatment Postpones Renal Insufficiency in Diabetic Nephropathy

The effect of long-term, aggressive, antihypertensive treatment on kidney function in diabetic nephropathy was studied prospectively in 11 insulin-dependent diabetic patients (mean age, 30 years). Renal function was assessed every 4 months by measurement of glomerular filtration rate (GFR) (single-bolus 51Cr-EDTA technique) and by albuminuria (radial immunodiffusion). During the median pretreatment period of 2.4 years (range, 1.9 to 5.5 years), the GFR decreased significantly and albuminuria and the arterial blood pressure increased significantly. During the 9.7-year (range, 2.8 to 10.4 year) period of antihypertensive treatment with metoprolol, hydralazine, and furosemide, the arterial blood pressure decreased from 143/96 mm Hg to 130/84 mm Hg and albuminuria decreased from 1,038 micrograms/min to 547 micrograms/min. The rate of decline in GFR decreased from 10.7 mL/min/yr (range, 5.3 to 17.5 mL/min/yr) before treatment to 2.5 mL/min/yr (range, 0.5 to 4.8 mL/min/yr) during treatment. The rate of decline in GFR is significantly smaller during the last 6 years compared with the first 3 years in patients who received long-term antihypertensive treatment (> or = 9 years). One patient died from acute myocardial infarction (GFR, 46 mL/min/1.73 m2). Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy.

Vitamin D levels and mortality in type 2 diabetes.

OBJECTIVE To evaluate vitamin D as a predictor of all-cause and cardiovascular mortality and risk of progression to micro- or macroalbuminuria in type 2 diabetic patients. RESEARCH DESIGN AND METHODS In a longitudinal observational follow-up study, 289 type 2 diabetic patients with normoalbuminuria (n = 172), microalbuminuria (n = 73), and macroalbuminuria (n = 44) at baseline were followed for a median (range) of 15.0 (0.2–23) years. Mean ± SD age was 54 ± 9 years. Plasma 25-hydroxyvitamin D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry on baseline samples. Severe vitamin D deficiency was defined as the lower 10th percentile (<13.9 nmol/l). RESULTS Median (range) vitamin D level was 35.7 (5–136.7) nmol/l. Vitamin D levels were not associated with age, sex, estimated glomerular filtration rate, urinary albumin excretion rate (UAER), or A1C at baseline, but low levels were weakly associated with elevated systolic blood pressure (R = 0.13, P = 0.03). During follow-up, 196 (68%) patients died. All-cause mortality was increased in patients with severe vitamin D deficiency (hazard ratio 1.96 [95% CI 1.29–2.98]). The association persisted after adjustment for UAER, A1C, diabetes duration, and conventional cardiovascular risk factors (2.03 [1.31–3.13]). Severe vitamin D deficiency was associated with increased cardiovascular mortality (1.95 [1.11–3.44]), and the association persisted after adjustment (1.90 [1.15–3.10]). Severe vitamin D deficiency at baseline did not predict progression to micro- or macroalbuminuria. CONCLUSIONS In type 2 diabetic patients, severe vitamin D deficiency predicts increased risk of all-cause and cardiovascular mortality, independent of UAER and conventional cardiovascular risk factors. Whether vitamin D substitution improves prognosis remains to be investigated.

QTc interval length and QT dispersion as predictors of mortality in patients with non-insulin-dependent diabetes

Patients with non-insulin-dependent diabetes (NIDDM) are at independent risk of cardiovascular death. The reason is only partially understood. The aim of our study was therefore to evaluate the impact of corrected QT interval length (QTc) and QT dispersion (QT-disp) on mortality in a cohort of 324 Caucasian NIDDM patients. A resting 12-lead ECG was recorded at baseline. Maximum (QT-max) and minimum QT (QT-min) intervals were measured, and QT-max was corrected for heart rate (QTc-max). QT-disp was defined as the difference between QT-max and QT-min. QTc-max was 454 (376-671) ms½ (median (range)) and QT-disp 61 (0-240) ms. Prolonged QTc interval (PQTc), defined as QTc-max>440 ms½, was present in 67% of the patients and prolonged QT-disp (PQT-disp), defined as QT-disp>50 ms, was present in 51%. During the 9-year follow-up period, 100 patients died (52 from cardiovascular diseases). Thirty-seven percent of the patients with PQTc died compared with 17% with normal QTc interval (p<0.001). The Cox proportional hazard model, including putative risk factors at baseline, revealed the following independent predictors of all cause mortality; QTc-max (p<0.05), age (p<0.0001), albuminuria (p<0.01), retinopathy (p><0.01), HbA1c (p<0.05), insulin treatment (p<0.01), total cholesterol (p<0.01), serum creatinine (p<0.05) and presence of cardiac heart disease based on Minnesota coded ECG (p<0.001). Whereas QT-disp was not a predictor. QTc-max interval was an independent predictor of cardiovascular mortality. Our study showed a high prevalence of QTc and QT-disp abnormalities and indicated that QTc-max but not QT-disp is an independent predictor of all cause and cardiovascular mortality in NIDDM patients.