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H H Parving

Publications and source records attributed to H H Parving.

At least 37 records · Page 2Linked to original sources
PubMed2001

Hypertension and diabetes: the scope of the problem.

Cardiovascular and renal diseases in diabetes stem from an accelerated form of atherosclerosis in both small and large blood vessels. Diabetic nephropathy is a clinical hallmark of microangiopathy and often leads to end-stage renal failure. Significantly, microalbuminuria is an independent predictor of cardiovascular morbidity and mortality in both the diabetic and non-diabetic population. In diabetic patients, it is also strongly associated with proliferative retinopathy, neuropathy and hypertension. Effective blood pressure reduction in patients with type 2 diabetes and diabetic nephropathy is known to reduce albuminuria, delay the progression of diabetic nephropathy, postpone renal failure and improve survival. These benefits have been demonstrated with a variety of blood pressure-lowering agents, including beta-blockers, calcium channel blockers, diuretics and angiotensin-converting enzyme (ACE) inhibitors. Less is known about the renal effects of the newest class of antihypertensive agents, the angiotensin II receptor antagonists (AIIRAs). Irbesartan is an AIIRA that provides antihypertensive efficacy comparable to ACE inhibitors but with superior tolerability. The PRogram for Irbesartan Mortality and morbidity Evaluations (PRIME) is an important morbidity and mortality program encompassing the Irbesartan Diabetic Nephropathy Trial (IDNT) and the IRbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients (IRMA II) study. PRIME is evaluating the effects of irbesartan in preventing diabetic nephropathy and end-stage renal failure and in reducing cardiovascular events in high-risk hypertensive patients with type 2 diabetes. The trials were completed at the end of 2000.

Albuminuria↗
PubMed2001

Elevated levels of plasma von Willebrand factor and the risk of macro- and microvascular disease in type 2 diabetic patients with microalbuminuria.

BACKGROUND: The purpose of this study was to examine the concept suggesting that microalbuminuria in combination with high levels of plasma von Willebrand factor is a stronger predictor for cardiovascular disease and microvascular complications than microalbuminuria alone in type 2 diabetic patients. METHODS: One hundred and sixty patients with type 2 diabetes mellitus and persistent microalbuminuria were followed for an average of 3.8 (SD 0.3) years. 70% of the patients were treated with angiotensin converting enzyme (ACE)-inhibitors. Patients in this subanalysis were divided into two groups according to baseline plasma von Willebrand factor levels below or above the median. The main outcome was cardiovascular disease (cardiovascular mortality, non-fatal stroke, non-fatal myocardial infarction, coronary artery bypass graft and revascularization or amputation of legs), progression to diabetic nephropathy or progression in diabetic retinopathy. RESULTS: At baseline the two groups were comparable for HbA(1c), fasting levels of s-total-cholesterol, s-HDL-cholesterol and s-triglycerides, systolic and diastolic blood pressure, gender, known diabetes duration, smoking habits, previous cardiovascular disease and antihypertensive therapy as well as retinopathy. Odds ratio for cardiovascular disease was 1.11 (95% CI 0.45-2.73, P=0.82) (multiple logistic regression), odds ratio for progression to nephropathy was 1.08 (0.41-2.85, P=0.87) and odds ratio for progression in retinopathy was 0.96 (0.46-2.00, P=0.92), all with plasma von Willebrand factor levels above the median. CONCLUSIONS: Our results do not support the suggestion that the combination of high plasma levels of von Willebrand factor and microalbuminuria is a stronger predictor for cardiovascular disease, progression to diabetic nephropathy or progression in diabetic retinopathy than microalbuminuria alone in patients with type 2 diabetes and persistent microalbuminuria.

Adult↗
PubMed2001

Renal function and structure in albuminuric type 2 diabetic patients without retinopathy.

BACKGROUND: In type 2 diabetic patients without retinopathy the cause of albuminuria is heterogeneous and our knowledge of the relationship between kidney structure and function in these patients is limited. Therefore, a long-term study evaluating the structural-functional relationship in albuminuric type 2 diabetic patients without retinopathy was performed. METHODS: Mesangial volume of total glomerular volume (Vv (mes/glom)), fractional area of focal interstitial fibrosis and tubular atrophy of cortical area (FF) and percentage of sclerosed glomeruli (S/G) were measured on kidney biopsies from 49 type 2 diabetic patients without retinopathy. Glomerular filtration rate (GFR) was determined at least 3 times (median 8 (range 3-20)) in each patient. Patients were followed for 7.0 (1.1-17) years. Albuminuria and blood pressure were measured every 3-6 months. RESULTS: Biopsies revealed diabetic glomerulopathy (DG-group) in 69% of the patients (27 male/7 female) and normal glomerular structure (n=9) or glomerulonephritis (n=6) were found in 31% (13 male/2 female) (NDG-group). In the DG-group GFR decreased from 97+/-5 to 66+/-5 ml/min/1.73 m(2) (mean+/-SE) (P<0.001), with a rate of decline in GFR of 5.3+/-0.8 ml/min/year and in the NDG-group from 93+/-7 to 74+/-11 ml/min/1.73 m(2) (P<0.01), with a rate of decline in GFR of 3.2+/-0.9 ml/min/year, P=0.09 between groups. Mean arterial blood pressure decreased from 109+/-2 to 100+/-2 mm Hg (P<0.001) (DG-group) and remained unchanged in the NDG-group. An association between Vv (mes/glom) and rate of decline in GFR was revealed mainly in the NDG-group (DG-group; r=0.31, P=0.07 and NDG-group; r=0.74, P<0.01). Furthermore, the rate of decline in GFR seemed to be associated with FF in the NDG group (r=0.48, P=0.07). Percentage of S/G was not associated with the rate of decline in GFR. Vv (mes/glom) was associated with mean albuminuria during follow-up in the DG group; r=0.38, P<0.03 (NDG group; r=0.51, P=0.09). Albuminuria was an independent predictor of the rate of decline in GFR in both groups (DG-group; r=0.40, P<0.05 and NDG-group; r=0.61, P<0.01). CONCLUSIONS: Our study revealed a tendency to a faster rate of decline in GFR in the DG-group compared to the much smaller NDG-group, characterized by marked heterogeneity of the underlying kidney lesions and rate of GFR loss. A large mesangial volume fraction was associated with increased albuminuria and loss in GFR. Albuminuria acted as a progression promoter in both groups.

Albuminuria↗
PubMed2001

Diabetic microvascular complications are not associated with two polymorphisms in the GLUT-1 and PC-1 genes regulating glucose metabolism in Caucasian type 1 diabetic patients.

BACKGROUND: An XbaI polymorphism in the gene encoding the glucose transporter, GLUT-1, is associated with development of diabetic nephropathy in Chinese type 2 diabetic patients. In addition, an amino acid variant (K121Q) in the gene encoding the glycoprotein plasma cell differentiating antigen (PC-1), a specific inhibitor of insulin receptor signalling, has been reported to predict a faster progression of nephropathy in Italian and British type 1 diabetic patients. METHODS: The XbaI and K121Q polymorphisms were determined by PCR-RFLP in Danish type 1 diabetic patients with nephropathy (122 men/77 women, age 40.9+/-9.6 years, diabetes duration 27+/-8 years) and type 1 diabetic patients with persistent normoalbuminuria (118 men/74 women, age 42.7+/-10.2 years, diabetes duration 26+/-9 years). Proliferative retinopathy was present in 156 patients (40%), while 67 patients (17%) had no diabetic retinopathy. RESULTS: There were no differences in the frequency of GLUT-1 XbaI genotypes between type 1 diabetic patients with diabetic nephropathy and type 1 diabetic patients with normoalbuminuria: 72 (41%)/87 (50%)/16 (9%) vs 94 (49%)/74 (39%)/24 (13%) had GLUT-1 XbaI +/+, +/- or -/- genotype respectively (NS). The frequency of PC-1 KK, KQ and QQ genotypes were 141 (71%)/52 (26%)/6 (3%) vs 138 (73%)/45 (24%)/7 (4%) in patients respectively with and without nephropathy (NS). Neither were associations between the investigated polymorphisms and simplex or proliferative retinopathy revealed. CONCLUSIONS: Neither the PC-1 K121Q nor the GLUT-1 XbaI polymorphism contribute to the genetic susceptibility of diabetic microvascular complications in Danish type 1 diabetic patients.

Adolescent↗
PubMed2001

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.

Angiotensin Receptor Antagonists↗
PubMed2001

Polymorphism screening of four genes encoding advanced glycation end-product putative receptors. Association study with nephropathy in type 1 diabetic patients.

Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes encoding these AGE receptors in 48 patients with type 1 diabetes and investigated the identified polymorphisms (n = 19) in 199 type 1 diabetic patients with nephropathy and 193 type 1 diabetic patients without nephropathy. Overall, none of the polymorphisms was strongly associated with nephropathy. The minor allele of a polymorphism located in the promoter region of the RAGE gene (C-1152A) conferred a weak protective effect (P < 0.05) and was associated with a longer duration of nephropathy-free diabetes (P = 0.08).

5' Untranslated Regions↗
PubMed2001

Remission of nephrotic-range albuminuria in type 1 diabetic patients.

OBJECTIVE: To evaluate the cumulative incidence of nephrotic-range albuminuria (NRA), the frequency of remission, and the impact on progression, we analyzed data from a prospective cohort study of type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: All of the albuminuric type 1 diabetic patients (n = 321, 121 women), who had at least yearly measurements of glomerular filtration rate (GFR) with a (51)Cr-EDTA plasma clearance technique and were followed for at least 3 years, were evaluated. NRA, defined as persistent albuminuria >2,500 mg/24 h, occurred in 126 patients (35 women) aged (mean +/- SD) 34 +/- 8 years, with duration of diabetes 22 +/- 8 years and follow-up time from onset of NRA (median [range]) 8.7 (3.0-20.9) years. Remission of NRA was defined as sustained albuminuria <600 mg/24 h for at least 1 year. RESULTS: The cumulative incidence of NRA was 39%. Remission was induced in 28 of 126 (22%) patients; 21 were predominantly treated with ACE inhibitors, 7 with non-ACE inhibitor medications. Remission lasted 3.6 (1.0-18.1) years. More women (37%) than men (16%) obtained remission (P = 0.01). In the remission group compared with the no-remission group, mean arterial blood pressure (mean +/- SEM) was reduced (102 +/- 1 vs. 106 +/- 1 mmHg, P < 0.01), the rate of decline in GFR was diminished (3.8 +/- 0.6 vs. 7.5 +/- 0.5 ml x min(-1) x year(-1), P < 0.001), and serum cholesterol was lower (5.3 +/- 0.2 vs. 6.1 +/- 0.1 mmol/l, P < 0.01) during the whole follow-up period. No difference in glycemic control was found between groups (HbA(1c) 9.2 vs. 9.4%, NS). CONCLUSIONS: In contrast to observations made before the use of antihypertensive treatment, our prospective observational study suggests that aggressive antihypertensive treatment with and without ACE inhibitors can induce long-lasting remission in a sizeable fraction of type 1 diabetic patients with NRA. The group of patients obtaining remission is characterized by slow progression of diabetic nephropathy and improved cardiovascular risk profile.

Adult↗
PubMed2000

Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin angiotensin system on risk of developing diabetic nephropathy in type I diabetic patients.

AIMS/HYPOTHESIS: Reports on a putative synergism between poor glycaemic control and carriage of the angiotensin II type 1 receptor (AGTR1) C1166-allele and risk of diabetic nephropathy have been conflicting. Therefore, we investigated the interaction between long-term glycaemic control and three polymorphisms in the genes coding for AGTR1 (A1166-->C), angiotensin converting enzyme (ACE/ID) and angiotensinogen (M235T) on risk of developing diabetic nephropathy. Furthermore, we investigated the relation between a random measurement and long-term measurements of haemoglobin A1c (HbA1c). METHODS: We studied Caucasian patients with Type I (insulin-dependent) diabetes mellitus and nephropathy (120 men 74 women, age 41.1 +/- 9.6 years, diabetes duration 28 +/- 8 years) and long-standing Type I diabetic patients with persistent normoalbuminuria (112 men 69 women, age 42.5 +/- 10.0 years, diabetes duration 27 +/- 9 years). Genotyping was PCR-based and metabolic control estimated from all measurements of HbA1c done in each patient [average (range) n = 31 (6-74)]. The median observation time (range) was 13.5 (2-14) years. RESULTS: Type I diabetic patients with a history of poor glycaemic control (HbA1c above the median, 8.7%) had an increased risk of diabetic nephropathy compared with patients with a better metabolic control, OR (95% CI): 9.2 (5.8-14.7). The magnitude of this risk was similar in carriers and non-carriers of the mutations. The risk of nephropathy in patients with HbA1c above compared with below the median in carriers of the mutant C1166-allele, D-allele, or T235-allele were 7.6 (95% CI: 3.9-14.8), 10.4 (6.0-17.8) and 9.8 (5.4-17.9), respectively. A significant correlation (r = 0.74, p < 0.001) existed between a random and long-term measurements of HbA1c with a small mean difference (limits of agreement) [0.2 (-1.8 to 2.1)%] between the two estimates. CONCLUSION/INTERPRETATION: Poor metabolic control is a major risk factor for diabetic nephropathy in Caucasian Type I diabetic patients. This risk was similar in carriers and non-carriers of the mutant alleles of the AGTR1 (A1166-->C), ACE/ID and angiotensinogen-M235T polymorphisms. The HbA1c value measured at random reflects rather closely average long-term HbA1c values.

Adolescent↗
PubMed2000

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.

Adult↗
PubMed2000

Causes of albuminuria in patients with type 2 diabetes without diabetic retinopathy.

BACKGROUND: The causes of albuminuria in patients with type 2 diabetes are heterogeneous and are scantily investigated, particularly if the patient has a lack of diabetic retinopathy. Therefore, we evaluated the structural background of albuminuria in a large consecutive group of Caucasian patients with type 2 diabetes without retinopathy. METHODS: Three hundred forty-seven consecutive patients with type 2 diabetes with persistent albuminuria (>300 mg/24 h) were recorded. Fundus photo (80%) and ophthalmoscopy were performed. Ninety-three (27%) had no retinopathy, and a kidney biopsy was performed in 52 (56%) of these patients. An insufficient tissue sample was obtained in one patient. The biopsies were evaluated by three masked nephropathologists. RESULTS: The biopsies revealed diabetic glomerulopathy in 69% of the patients (28 males and 7 females), while the remaining 31% (95% CI, 18 to 44) had either nondiabetic glomerulopathies such as glomerulonephritis (N = 7, 6 males and 1 female, 13%) or normal glomerular structure (N = 9, 7 males and 2 females, 18%). No significant differences in sex, age (56 +/- 8 vs. 53 +/- 10 years, mean SD), body mass index (30 +/- 4 vs. 31 +/- 8 kg/m2), known duration of diabetes (6 +/- 6 vs. 4 +/- 3 years), GFR (95 +/- 29 vs. 89 +/- 31 mL/min/1.73 m2), albuminuria (1304 +/- 169 to 4731 vs. 1050 +/- 181 to 5176 mg/24 hours), blood pressure (150/87 +/- 16/9 vs. 145/89 +/- 16/9 mm Hg), prevalence of hypertension (89 vs. 100%), hemoglobin A1c (8.2 +/- 1.6% vs. 9.0 +/- 2.5%), and serum total cholesterol (7.1 +/- 2.4 vs. 6.3 +/- 1.6 mmol/L) were found between patients with and without diabetic glomerulopathy. CONCLUSIONS: Albuminuric patients with type 2 diabetes without diabetic retinopathy have a prevalence of biopsies with normal glomerular structure or nondiabetic kidney diseases of approximately 30%. A separation between diabetic and nondiabetic glomerular lesions was not possible based on demographic, clinical, or laboratory data. Consequently, such patients may require further evaluation, including a kidney biopsy.

Adult↗
PubMed2000

Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy.

BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition. CONCLUSION: The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.

Adult↗
PubMed2000

Hyperglycaemia enhances renal magnesium excretion in type 1 diabetic patients.

Magnesium depletion is a common feature of diabetes mellitus, apparently related to glycaemic control. The aim of the study was to investigate the isolated effect of hyperglycaemia upon renal magnesium excretion. Urinary magnesium excretion rates were measured in 10 patients with Type 1 diabetes mellitus on two different days with different levels of blood glucose concentration but equal plasma insulin concentration. On a hyperglycaemic day, an i.v. infusion of 20% glucose was started at the end of a euglycaemic baseline period, increasing blood glucose concentration from 5.3 mmol/L to 12.3 mmol/L. There was no major glucosuria. On the hyperglycaemic day the renal magnesium excretion and clearance were raised by a factor of 2.4 compared to the euglycaemic day. Plasma magnesium concentration decreased 3% during hyperglycaemia. In conclusion, blood glucose excursions influence magnesium homeostasis independently of insulin levels in Type 1 diabetic patients. This effect is primarily due to an increased renal magnesium clearance during hyperglycaemia.

Adult↗
PubMed2000

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) ms(1/2) (median (range)) and QT-disp 61 (0-240) ms. Prolonged QTc interval (PQTc), defined as QTc-max > 440 ms(1/2), 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.

Albuminuria↗
PubMed2000

Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy.

BACKGROUND: A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of diabetic micro- and macrovascular complications. METHODS: We studied 198 type 1 diabetic patients with diabetic nephropathy [121 men, age (mean+/-SD) 41+/-10 years, diabetes duration 28+/-8 years] and 192 patients with persistent normoalbuminuria (118 men, age 43+/-10 years, diabetes duration 27+/-9 years). RESULTS: Male patients with nephropathy had elevated plasma PAI-1 levels [geometric mean (95% CI)], 70 (62-79) ng/ml, compared with normoalbuminuric men, 43 (38-47) ng/ml, P<0.001. Even though nephropathic patients with the 4G4G genotype tended to have higher plasma PAI-1 levels, P=0.06, no difference in allele frequency (4G/5G) was seen between patients with and without nephropathy: 0.538/0.462 vs 0.539/0.461, respectively. Nor did ApoE allele frequencies (epsilon2/epsilon3/epsilon4) differ between nephropathic and normoalbuminuric patients: 0.099/0.749/0. 152 vs 0.081/0.745/0.174, respectively. Genotype distributions were also similar, n.s. Coronary heart disease was more prevalent (36%) among nephropathic patients carrying the atherogenic epsilon4-allele compared with 12% in patients with the epsilon3,epsilon3 genotype, P<0.001. No associations between diabetic retinopathy and PAI-1 or ApoE polymorphisms were observed, n.s. CONCLUSIONS: The ApoE polymorphism may accelerate the development of coronary heart disease often seen in Caucasian patients with type 1 diabetes and diabetic nephropathy, a condition characterized by elevated plasma PAI-1 in men. Neither the PAI-1 nor the ApoE gene polymorphism contributes to the genetic susceptibility to diabetic nephropathy or retinopathy.

Adult↗
PubMed2000

Glomerular permselectivity in early stages of overt diabetic nephropathy.

BACKGROUND: Impairment of glomerular size selectivity has been demonstrated by the dextran-sieving technique in nephropathic diabetics with heavy, but not mild proteinuria. The purpose of the present study was to determine whether such a barrier defect could be demonstrated with mild proteinuria by substituting Ficoll 70, a polysucrose, for dextran as a probe of the filtration barrier. METHODS: Differential solute clearances were performed in 12 individuals with early diabetic nephropathy on two occasions: after 60 days of treatment with losartan 50 mg daily or a placebo. An uncharged preparation of nonreabsorbable Ficoll 70 was infused along with inulin. Fractional clearance (theta) of Ficoll of discrete size was determined after separating molecules in urine and plasma in narrow 2 A fractions over a 20 to 60 A radius interval by size exclusion high-performance liquid chromatography (HPLC). A hydrodynamic theory of hindered ficoll transport through water-filled pores was used to characterize the pore size distribution of the glomerular barrier. RESULTS: The theta for Ficoll molecules with radii> 50 A was selectively enhanced in placebo-treated diabetic nephropathy versus corresponding theta in healthy control subjects (N = 12). Computations revealed a lower distribution of glomerular pores that was unaltered in nephropathic diabetics. However, an upper distribution of large, shunt-like pores was more prominent, exceeding healthy controls by one order of magnitude in diabetic nephropathy (P = 0.01). A trend to lower theta for Ficoll in the 56 to 60 A radius range during losartan therapy is computed to have lowered the fraction of shunted filtrate by 26 to 44%, depending on whether glomerular pressure declined. The corresponding reduction in theta for endogenous albumin, IgG, and IgG4 was by 19 to 23% (P < 0.05). CONCLUSION: Our findings suggest that shunt-like defects, partially reversible by angiotensin II blockade, are present early in the course of diabetic nephropathy. We estimate that such defects can account for immunoglobulinuria in this disorder. Additional impairment of either charge- or shape-selectivity must be invoked to explain the observed level of albuminuria, however.

Adult↗
PubMed2000

Cardiovascular morbidity and early mortality cluster in parents of type 1 diabetic patients with diabetic nephropathy.

OBJECTIVE: A familial predisposition was proposed to be a determinant of the increased morbidity and mortality from cardiovascular disease in type 1 diabetic patients with diabetic nephropathy. The insertion allele of an insertion/deletion polymorphism in the ACE (ACE/ID) gene seems to protect against coronary heart disease in nondiabetic and diabetic subjects. The aim of the present study was to evaluate these hypotheses in parents of a large group of type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: We investigated cardiovascular morbidity and mortality of parents of 163 type 1 diabetic patients with nephropathy and parents of 163 sex- and age-matched normoalbuminuric patients with type 1 diabetes. RESULTS: Kaplan-Meier curves showed that total parental mortality was significantly increased in parents of type 1 diabetic patients with nephropathy (121 of 244 [ approximately 50%] ) as compared with parents of normoalbuminuric type 1 diabetic patients (119 of 269 [approximately 44%]) (P = 0.008 [log-rank test]) partially due to an increase in cardiovascular deaths (48 of 244 [approximately 20%] vs. 42 of 269 [approximately 16%], P<0.05). In addition, more patients with nephropathy, as compared with the normoalbuminuric group, had at least one parent with fatal/nonfatal cardiovascular disease (46% [95% CI 38-54] vs. 36% [28-44], P = 0.05). Fathers of patients homozygous for the I-allele of the ACE/ID polymorphism had significantly less myocardial infarction as compared with other genotypes (P = 0.03), regardless of the nephropathic state of the offspring. CONCLUSIONS: Cardiovascular morbidity and early mortality clusters in parents of type 1 diabetic patients with diabetic nephropathy The ACE/ID polymorphism helps explain the increased morbidity from cardiovascular disease.

Adult↗
PubMed2000

Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy.

OBJECTIVE: To compare the long-term effect on kidney function of a long-acting calcium antagonist (nisoldipine) versus a long-acting ACE inhibitor (lisinopril) in hypertensive type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: We performed a 4-year prospective, randomized, double-dummy controlled study comparing nisoldipine (20-40 mg once a day) with lisinopril (10-20 mg once a day). The study was double-blinded for the first year and single-blinded thereafter. The study included 51 hypertensive type 1 diabetic patients with diabetic nephropathy. Three patients dropped out during the first month; results for the remaining 48 patients are presented. RESULTS: At baseline, the two groups were comparable: glomerular filtration rate (GFR) was 85 +/- 5 and 85 +/- 6 ml x min(-1) x [1.73 m](-2); mean 24-h ambulatory blood pressure was 108 +/- 3 and 105 +/- 2 mmHg, and albuminuria was 1,554 mg/24 h (95% CI 980-2,465) and 1,033 mg/24 h (760-1,406) in the lisinopril and nisoldipine groups, respectively. Mean 24-h arterial blood pressure during the study did not differ between the lisinopril and nisoldipine groups (100 +/- 2 and 103 +/- 1 mmHg, respectively). The time-course of albuminuria differed between groups (P < 0.001). Whereas initiation of treatment with lisinopril resulted in a reduction from baseline albuminuria by 52% (95% CI 14-73), albuminuria in the nisoldipine group did not change throughout the study GFR declined in a biphasic manner with an initial (0-6 months) reduction of 1.3 +/- 0.3 ml x min(-1) x month(-1) in the lisinopril group compared with 0.2 +/- 0.4 ml x min(-1) x month(-1) in the nisoldipine group (P < 0.01). The subsequent sustained decline (6 to 48 months or the end of treatment) was identical in the two groups: 0.5 +/- 0.1 ml min(-1) x month(-1) (NS). Two patients in the lisinopril group and three patients in the nisoldipine group entered therapy for end-stage renal failure. CONCLUSIONS: Long-term treatment with lisinopril or nisoldipine has similar beneficial effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients.

Adult↗