Smoking is related to albuminuria and abnormal renal function in nondiabetic persons

BACKGROUND: Smoking induces albuminuria and accelerates progression to renal failure in persons with diabetes, but little is known about the relation between smoking and renal function in nondiabetic persons. OBJECTIVE: To investigate whether smoking is related to albuminuria and abnormal renal function in nondiabetic persons. DESIGN: Cross-sectional study. SETTING: Groningen, The Netherlands. PARTICIPANTS: 7476 participants in the PREVEND (Prevention of REnal and Vascular ENd stage Disease) Study. MEASUREMENTS: Microalbuminuria and high normal albuminuria were defined as urinary albumin excretion of 30 to 300 mg/24 h and 15 to 30 mg/24 h, respectively. Elevated or decreased glomerular filtration rate (GFR) was defined as a creatinine clearance that exceeded or was less than two times the standard deviation of the mean value in nondiabetic, nonsmoking participants who had an albumin excretion of 0 to 15 mg/24 h, adjusted for age and sex. RESULTS: Current smokers had a higher median albumin excretion than nonsmokers and were more likely to have microalbuminuria and high normal albuminuria with elevated or decreased GFR. After adjustment for several potential confounding factors, persons who smoked 20 or fewer cigarettes/d and persons who smoked more than 20 cigarettes/d, respectively, showed a dose-dependent association between smoking and high normal albuminuria (relative risk, 1.33 [95% CI, 1.10 to 1.61] and 1.98 [CI, 1.49 to 2.64]), microalbuminuria (relative risk, 1.92 [CI, 1.54 to 2.39] and 2.15 [CI, 1.52 to 3.03]), elevated GFR (relative risk, 1. 82 [CI, 1.31 to 2.53] and 1.84 [CI, 1.12 to 3.02]), and decreased GFR (relative risk, 1.53 [CI, 1.04 to 2.24] and 1.83 [CI, 1.05 to 3. 20]), respectively. Quitting smoking was associated only with microalbuminuria. CONCLUSIONS: Smoking is associated with albuminuria and abnormal renal function. However, these associations are less pronounced or absent in former smokers.     

Increased urinary type IV collagen marks the development of glomerular pathology in diabetic d/db mice.

The diabetic db/db mouse exhibits increased albumin excretion soon after the onset of obesity and hyperglycemia, and later manifests glomerular mesangial matrix expansion resembling that found in human diabetic nephropathy. Since the glomerular lesion in this rodent model of type 2 diabetes is associated with renal overexpression of mRNA encoding type IV collagen, we postulated that changes in the urinary excretion of collagen IV may reflect developing glomerular pathology. To explore this hypothesis, we monitored urinary collagen IV (measured by immunoassay) in db/db mice during the course of evolution of nephropathy. At age 8 weeks, collagen IV excretion was not different in diabetic compared to nondiabetic animals despite marked albuminuria, but was significantly increased in db/db compared to db/m mice at age 12 and 16 weeks. Serum levels of collagen IV did not significantly differ between normal versus diabetic mice at any age. Glomerular morphometry revealed mesangial matrix expansion at age 12 weeks, coincident with the rise in collagen IV excretion, which became more marked at age 16 weeks in association with reduced creatinine clearance and elevated serum creatinine. The findings suggest that increased urinary type IV collagen is a better indicator than albuminuria of developing glomerular matrix accumulation that results in compromised renal filtration function.     

Increased urinary type IV collagen marks the development of glomerular pathology in diabetic d/db mice

The diabetic db/db mouse exhibits increased albumin excretion soon after the onset of obesity and hyperglycemia, and later manifests glomerular mesangial matrix expansion resembling that found in human diabetic nephropathy. Since the glomerular lesion in this rodent model of type 2 diabetes is associated with renal overexpression of mRNA encoding type IV collagen, we postulated that changes in the urinary excretion of collagen IV may reflect developing glomerular pathology. To explore this hypothesis, we monitored urinary collagen IV (measured by immunoassay) in db/db mice during the course of evolution of nephropathy. At age 8 weeks, collagen IV excretion was not different in diabetic compared to nondiabetic animals despite marked albuminuria, but was significantly increased in db/db compared to db/m mice at age 12 and 16 weeks. Serum levels of collagen IV did not significantly differ between normal versus diabetic mice at any age. Glomerular morphometry revealed mesangial matrix expansion at age 12 weeks, coincident with the rise in collagen IV excretion, which became more marked at age 16 weeks in association with reduced creatinine clearance and elevated serum creatinine. The findings suggest that increased urinary type IV collagen is a better indicator than albuminuria of developing glomerular matrix accumulation that results in compromised renal filtration function.     

Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension

Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg (P for all <0.001), respectively, without significant changes in the control group. SBP reduction after 6 months correlated with SBP baseline values (r=-0.46; P<0.001). There were no renal artery stenoses, dissections, or aneurysms during 6 months of follow-up. Renal resistive index decreased from 0.691±0.01 at baseline to 0.674±0.01 and 0.670±0.01 (P=0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension.     

Randomized comparison of pitavastatin and pravastatin treatment on the reduction of urinary albumin in patients with type 2 diabetic nephropathy

The effect of pitavastatin and pravastatin treatment on renal function was compared in type 2 diabetic patients with nephropathy in a randomized, controlled, open-label, parallel and multi-centre study. Type 2 diabetic patients with modest renal impairment (serum creatinine level <1.4 mg/dl) accompanied by albuminuria (30-600 mg/g creatinine) were randomly assigned to receive 2 mg of pitavastatin (n = 44) or 10 mg of pravastatin (n = 43) for 12 months. At 12 months, pitavastatin significantly reduced urinary albumin-to-creatinine ratio than pravastatin in subjects with macroalbuminuria (-67.2% vs. +14.5%, p = 0.0040), but not in subjects with microalbuminuria. There was no significant difference in the change in estimated glomerular filtration rate between the two groups. Pitavastatin is more effective than pravastatin for the reduction of albuminuria in type 2 diabetic patients with early stage of diabetic nephropathy.     

Reversible acute renal failure and nephrotic syndrome in a Type 1 diabetic patient

Nephrotic syndrome is a condition commonly associated with end-stage renal disease secondary to diabetic nephropathy. It is usually associated with long-standing renal insufficiency, microalbuminuria, and overt proteinuria. We present a diabetic patient with acute oliguric renal failure and nephrotic syndrome. At presentation, he had a serum creatinine of 2.3 mg/dl, blood urea nitrogen (BUN) of 69 mg/dl, urinary protein excretion of 10.5 g/24 h, serum albumin of 1.3 g/dl, and a urine output < 400 cc/24 h. A renal biopsy was done and the renal pathology was compatible with early diabetic nephropathy. Despite intense diuretic therapy, the patient's renal condition did not improve, and peritoneal dialysis was started several months after diagnosis. After 8 months of dialysis therapy, the patient's renal parameters and urinary output spontaneously restored to normal limits (serum creatinine was 1.1 mg/dl, urinary albumin excretion was 411 mg/24 h, serum albumin was 4.3 g/dl, and normal urine output) and dialysis was discontinued. His renal function did not deteriorate after discontinuation of dialysis. We conclude that this patient's reversible acute renal failure and nephrotic syndrome were associated with minimal change disease and not due to diabetic nephropathy.     

Diabetic nephropathy

Diabetic nephropathy is the leading cause of chronic renal disease and a major cause of cardiovascular mortality. Diabetic nephropathy has been categorized into stages: microalbuminuria and macroalbuminuria. The cut-off values of micro- and macroalbuminuria are arbitrary and their values have been questioned. Subjects in the upper-normal range of albuminuria seem to be at high risk of progression to micro- or macroalbuminuria and they also had a higher blood pressure than normoalbuminuric subjects in the lower normoalbuminuria range. Diabetic nephropathy screening is made by measuring albumin in spot urine. If abnormal, it should be confirmed in two out three samples collected in a three to six-months interval. Additionally, it is recommended that glomerular filtration rate be routinely estimated for appropriate screening of nephropathy, because some patients present a decreased glomerular filtration rate when urine albumin values are in the normal range. The two main risk factors for diabetic nephropathy are hyperglycemia and arterial hypertension, but the genetic susceptibility in both type 1 and type 2 diabetes is of great importance. Other risk factors are smoking, dyslipidemia, proteinuria, glomerular hyperfiltration and dietary factors. Nephropathy is pathologically characterized in individuals with type 1 diabetes by thickening of glomerular and tubular basal membranes, with progressive mesangial expansion (diffuse or nodular) leading to progressive reduction of glomerular filtration surface. Concurrent interstitial morphological alterations and hyalinization of afferent and efferent glomerular arterioles also occur. Podocytes abnormalities also appear to be involved in the glomerulosclerosis process. In patients with type 2 diabetes, renal lesions are heterogeneous and more complex than in individuals with type 1 diabetes. Treatment of diabetic nephropathy is based on a multiple risk factor approach, and the goal is retarding the development or progression of the disease and to decrease the subject's increased risk of cardiovascular disease. Achieving the best metabolic control, treating hypertension (<130/80 mmHg) and dyslipidemia (LDL cholesterol <100 mg/dl), using drugs that block the renin-angiotensin-aldosterone system, are effective strategies for preventing the development of microalbuminuria, delaying the progression to more advanced stages of nephropathy and reducing cardiovascular mortality in patients with diabetes.     

Microalbuminuria: do we need a new threshold?

Microalbuminuria (30-300 mg of albumin/24 h) is a well-known independent risk factor for kidney and cardiovascular disease and of mortality in diabetic, hypertensive and in the general population. However, recent studies indicate that increased risk is observed at levels of albuminuria much lower than those currently employed to define microalbuminuria. Such low levels were shown to predict heart disease and death, independent of age, sex, renal function, diabetes, hypertension and lipids, in subjects with cardiovascular disease, hypertension and in the general population; as well as to predict progression to hypertension. Correction of obesity and metabolic derangements lowered levels of albuminuria below 30 mg/24 h to levels not associated with increased risk (5-7 mg/24 h). Despite the lack of outcome studies, there is substantial evidence to indicate that the threshold for defining microalbuminuria (that is, albuminuria associated with increased risk) should be lowered by nearly three to four-fold from the currently defined threshold. It would be advisable that clinical scores and future guidelines would consider including microalbuminuria at the lower rates as an independent risk factor, and as an indication for implementing early intervention. Unfortunately, and despite the abundance of evidence, albuminuria measurements are still underutilized in clinical practice.     

The effects of aminoguanidine on renal changes in a baboon model of Type 1 diabetes

BACKGROUND: The efficacy of aminoguanidine (AG) on primary prevention of diabetic nephropathy was investigated in a nonhuman primate model of Type 1 diabetes over a period of 4 years. METHODS: Adolescent male baboons (Papio hamadryas) were assigned to four groups: control, diabetic, and control and diabetic treated with AG. Diabetes was induced with streptozocin (60 mg/kg) and treated with insulin to maintain a mean HbA1c level of about 9%. AG was given subcutaneously (10 mg/kg) each day. All animals had annual renal biopsies and 24-h urine collections for measurements of glomerular basement membrane (GBM) thickness, fractional mesangium volume (FMV), albumin excretion rate (AER), and creatinine clearance. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were also determined. RESULT: The diabetic animals had increased GBM after 2 years of diabetes, but there was no increase in FMV over the study period. AG prevented the thickening of GBM at the 3- and 4-year time points. AG and diabetes synergistically increased the GFR. All diabetic animals developed increased albuminuria during the study although lower than the conventionally accepted microalbuminuria range. AG was not able to prevent this and, in fact, led to the nondiabetic animals also developing albuminuria. CONCLUSION: This is the first study to investigate the early use of AG in ameliorating renal damage in a primate model of Type 1 diabetes. The structural and functional changes in the kidney of these animals resemble those seen in the early stages of the human disease. AG was able to significantly reduce the thickening of GBM due to diabetes. This may suggest a potential role for this in primary prevention of diabetic nephropathy in the future.     

Structural basis of diabetic nephropathy in microalbuminuric NIDDM patients: a light microscopy study

Summary The objective of the study was to evaluate early structural changes occurring in patients with non-insulin-dependent diabetes mellitus (NIDDM) and microalbuminuria by light microscopy. Basal renal biopsy was performed in patients who were subsequently randomized to different antihypertensive treatments. Fourteen NIDDM patients aged 36–65 years (duration of diabetes 9 ± 7 years) with microalbuminuria (mean urinary albumin excretion 66 ± 49 μg/min) underwent percutaneous renal biopsy. Control biopsies were obtained from five patients of similar age undergoing nephrectomy for renal neoplasia with normal renal function and no history of renal disease. Control and diabetic biopsies were processed by light microscopy and stained with haematoxylin and eosin, periodic acid Schiff, Masson's trichrome and silver methenamine. The percentage of globally sclerotic glomeruli was evaluated. Glomerular volume was determined using perimeter analysis. A semiquantitative assessment (range 0 to 3 +) was made of mesangial sclerosis, interstitial fibrosis, tubular atrophy, arteriosclerosis and arteriolar hyalinosis. Glomerular volume was significantly increased in diabetic as compared to control glomeruli (3.2 ± 8 vs 1.8 ± 7, p < 0.01). Mesangial sclerosis (0.9 vs 0, p < 0.0001) and arteriolar hyalinosis (0.91 vs 0.2, p < 0.022) were significantly higher in diabetic compared to control subjects. No significant differences between diabetic and control subjects were found in the percentage of globally sclerotic glomeruli or in the extent of interstitial fibrosis, tubular atrophy and arteriosclerosis. Thus NIDDM patients with microalbuminuria show histological findings consistent with diabetic nephropathy characterized by glomerular hypertrophy, mesangial sclerosis and arteriolar hyalinosis. However, the renal histological changes are mild and appear less marked than in insulin-dependent diabetic patients. [Diabetologia (1996) 39: 1625–1628].     

Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor

Type I human diabetics and streptozotocin-induced diabetic mice with higher genetically determined levels of angiotensin-converting enzyme have an increased risk of developing nephropathy. However, previous experiments in mice and computer simulations indicate that modest increases in angiotensin-converting enzyme have minimal effects on blood pressure and angiotensin II levels, although bradykinin decreases significantly, inferring that bradykinin is critical for protecting the kidney in diabetics. Here, we confirm this inference by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor develop overt albuminuria, excreting the equivalent of >550 mg/day albumin in humans, which contrasts with the microalbuminuria (equivalent to <150 mg/day) seen in their simply diabetic littermates. The overt albuminuria is accompanied by a marked increase in glomerular mesangial sclerosis. The importance of bradykinin demonstrated here bears strongly on how current drugs reduce diabetic nephropathy and suggests that B2 receptor-specific agonists merit consideration in this context.     

Prorenin and renal function in NIDDM patients with normo- and microalbuminuria

Abstract. Objectives . To assess whether prorenin is elevated and perhaps a predictor of deteriorations in albuminuria and/or renal function in NIDDM patients with normo- and microalbuminuria. Design . A cross-sectional and a longitudinal study. Setting . Outpatient diabetic clinic. Subjects . Twenty-eight NIDDM patients (16 with normoalbuminuria, 12 with microalbuminuric) and 16 healthy subjects, matched for sex, age and BMI. Fifteen patients were reinvestigated after (mean [range]) 3.1 (2.1–4.3) years. Main outcome measures . Serum prorenin and renin, urinary albumin excretion rate, and glomerular filtration rate. Results . Serum prorenin was similar in both normoalbuminuric (116 × / ÷ 1.9 μU ml^-1(geometric mean × / ÷ antilog SD) and microalbuminuric (124 × / ÷ 1.7 μU ml^-1) as well as in healthy control subjects (90 × / ÷ 1.7 μU ml^-1). Prorenin did not correlate to either urinary albumin excretion rate or glomerular filtration rate. No difference between baseline and follow-up levels of albuminuria, glomerular filtration rate or prorenin were observed. The annual changes in albuminuria, glomerular filtration rate and prorenin were not correlated, and no correlation was found between baseline prorenin levels and annual changes in albuminuria or glomerular filtration rate. Conclusions . Serum prorenin levels are not elevated in either normoalbuminuric or microalbuminuric NIDDM patients, and serum prorenin is not a valid predictor of long-term changes in albuminuria in this patient group.     

Possible participation of a prostaglandin E1 analogue in the aggravation of diabetic nephropathy.

A relation between the progression of diabetic nephropathy and glomerular hyperfiltration has been speculated. We describe two cases of non-insulin-dependent diabetic males aged 55 and 59 years in whom diabetic nephropathy was aggravated during the administration of limaprost, a a prostaglandin E1 analogue with a vasodilatory action. We also observed a short-term effect of limaprost on renal hemodynamics in three cases with diabetic nephropathy. In case 1, one year after limaprost administration the serum albumin level fell from 3.6 to 2.6 g/dl and the serum creatinine level rose from 1.0 to 1.6 mg/dl. In case 2, 9 months after limaprost administration the serum albumin level fell from 3.6 to 2.9 g/dl and the serum creatinine level rose from 1.8 to 2.3 mg/dl. In the latter stages of limaprost administration, the downslopes of reciprocal serum creatinine against time appeared to be augmented in the two cases. After the 3-day administration of limaprost, the peripheral and renal blood flows, and the glomerular filtration rate (GFR) were observed to rise, but the filtration fraction (FF) and urinary protein output were elevated. Keeping in mind the pre-existing renal damage, the increases in GFR and FF suggested acceleration of compensatory glomerular hyperfiltration in less damaged surviving glomeruli. The sustained acceleration of hyperfiltration with long-term administration of limaprost as an exogenous vasodilatory prostaglandin was assumed to eventuate in the aggravation of diabetic nephropathy. Attention should be paid to drugs which increase GFR in patients with established diabetic nephropathy.     

Long-term decrease of microalbuminuria after one year of treatment with perindopril in hypertensive diabetic patients

We studied the effects of perindopril, an angiotensin converting enzyme (ACE) inhibitor administered during 12 months, on creatinine clearance, albuminuria and glycaemic control in diabetic subjects with mild to moderate hypertension. After 1 month placebo, 40 insulin-treated patients were divided into 3 groups based upon their urinary albumin excretion rate. Group 1 had a normoalbuminuria (less than 15 mg/24 h), group II had a microalbuminuria (15-150 mg/24 h) and group III had a macroproteinuria (greater than 150 mg/24 h and Albustix +). They were given perindopril 4 to 8 mg orally once daily, and received a stable diet. Diastolic blood pressure was normalized within the first 3 months in 80% of the patients. From these, 28 (14.7 and 7 from groups I, II and III respectively) were followed during a total active treatment period of 12 months. They were matched for age, duration of diabetes and hypertension, systolic and diastolic blood pressures, daily insulin dose, postprandial plasma C-peptide and quality of glycaemic control. Mean supine diastolic blood pressure was decreased by 15 and 18% at 1 and 12 months respectively. Heart rate was not significantly modified. At 3 months, plasma ACE activity was nearly totally inhibited while plasma renin activity was markedly increased. In patients of group II, microalbuminuria was reduced from 66 +/- 13 (mean +/- SEM after placebo) to 39 +/- 6 mg/24 h after 1 month perindopril and this effect was maintained at 12 months. In group I, albuminuria remained within the normal range. In group III, macroproteinuria was not consistently modified by perindopril. Creatinine clearance did not change and glycaemic control remained stable throughout the study in the 3 groups. No major side effects were observed. We conclude that perindopril normalizes blood pressure in a large majority of hypertensive diabetic patients without affecting the quality of diabetes control. It also induces a marked and sustained reduction of microalbuminuria in patients at risk of developing diabetic nephropathy.     

ACE inhibitor versus beta-blocker for the treatment of hypertension in renal allograft recipients

Angiotensin-converting enzyme (ACE) inhibitors have been shown to slow the progression of chronic renal failure. However, the value of ACE inhibitors for the treatment of hypertension in renal allograft recipients has not been established. ACE inhibitors dilate the efferent glomerular arteriole, an effect that may aggravate the decrease in glomerular filtration rate resulting from cyclosporine-induced vasoconstriction at the afferent glomerular arteriole. Therefore, the goal of this double-blind, randomized study was to compare the antihypertensive and renal effects of the ACE inhibitor quinapril with those of the beta-blocker atenolol in renal allograft recipients in whom hypertension developed 6 to 12 weeks after transplantation. All patients received cyclosporine as an immunosuppressant and had stable graft function (serum creatinine concentration, <220 micromol/L) at entry into the study. Twenty-nine patients who received quinapril (daily dose titrated between 2.5 and 20 mg) and 30 patients who received atenolol (daily dose titrated between 12.5 and 100 mg) completed the 24-month study. The two groups did not differ in age, sex ratio, height, and weight before entry into the study. Quinapril decreased diastolic blood pressure from 96+/-1 to 84+/-1 mm Hg (average throughout treatment period), and atenolol decreased diastolic blood pressure from 96+/-1 to 83+/-1 mm Hg. The serum creatinine concentration did not change significantly in either group after 24 months (129+/-8 micromol/L at entry and 148+/-19 micromol/L after 24 months in the quinapril group and 131+/-6 micromol/L at entry and 152+/-15 micromol/L after 24 months in the atenolol group; P=NS for both groups). After 24 months, the change in urinary albumin excretion from baseline was -10+/-15 mg/d in the quinapril group and 52+/-32 mg/d in the atenolol group (P=0.03). These results show that quinapril and atenolol are effective antihypertensive drugs when used after renal transplantation. Moreover, compared with atenolol, quinapril has no adverse effects on graft function. The relative reduction in albuminuria observed with quinapril as compared with atenolol could indicate a beneficial effect of quinapril on long-term graft function.     

Effect of 5-year enalapril therapy on progression of microalbuminuria and glomerular structural changes in type 1 diabetic subjects

A 5-year randomized, double blind, placebo-controlled study was carried out to determine the effect of the angiotensin-converting enzyme (ACE) inhibitor enalapril (E) on the progress of renal function and histology in subjects with type 1 diabetes and microalbuminuria. Seventy three type 1 diabetic patients with BP <140/90 and with persistent albuminuria (AER 20-200 microg/min) and normal renal function were randomly assigned to receive E (n=37) or placebo (n=36). A percutaneous renal biopsy was successfully performed in 69 patients and repeated in 59 patients after 5 years. The mean glomerular volume (MGV), mesangial volume (Vv mes) and glomerular basement membrane thickness (GBMT) were measured histomorphometrically. Before treatment, both groups had similar clinical characteristics, blood pressure, HbA(1c), albumin excretion rate (AER), glomerular filtration rate (GFR), serum creatinine and renal structural damage. Blood pressure was well controlled in both groups. In the patients treated with E, albuminuria decreased significantly (P<0.05) and only 8.1% (3/37) of subjects progressed to clinical albuminuria (AER >300 mg/24 h) compared with 30.5% (11/36) in the placebo group. The E treatment resulted in absolute risk reduction of 22.4 percentage points for the development of clinical albuminuria over a 5-year period (P<0.01). After 5 years of treatment, GBM thickness showed a consistent, though statistically insignificant, increase in the placebo group, whereas it remained stable in the E group. A significant increase in MGV and Vv mes was also observed in the placebo group on completion of the study. The present study indicates that long term therapy with E may decrease or delay the progression of structural glomerular damage in microalbuminuric diabetic subjects without marked hypertension (BP <140/90).     

雷公藤甲素治疗db／db糖尿病小鼠的疗效观察

目的:利用db/db小鼠验证雷公藤甲素对糖尿病肾脏损伤的治疗作用,探讨雷公藤甲素防治糖尿病肾病的机制. 方法:9周龄的db/db和db/m小鼠分为五组:(1)db/m正常对照组;(2)dh/dh糖尿病对照组;(3)缬沙坦治疗纽;(4)雷公藤甲素低剂最治疗组;(5)雷公藤甲素高剂繁治疗组.于4周、8周及12周测定各组24h尿白蛋白、血生化和体重.光镜观察肾小球病变,电镜观察足突改变,并作定量分析.免疫病理观察足细胞裂孔膜蛋白nephrin,足细胞损伤标志物desmin,炎症反应标志物单核细胞趋化蛋白1(MCP-1),氧化应激标志物4羟壬烯醛(4-HNE)的表达. 结果:db/db小鼠经雷公藤甲素治疗后蛋白尿下降,肾小球肥大和足细胞损伤减轻,肾组织炎症和氧化应激状态改善,同时高血脂和肥胖减轻.该作用随治疗时间延长,效果更加明显,且高剂量疗效优于低剂量.雷公藤甲素降低蛋白尿、改善肾小球肥大的作用与缬沙坦相似,但降低肾组织炎症和氧化应激的作用雷公藤甲素比缬沙坦更强. 结论:雷公藤甲索能明显降低dh/db小鼠尿蛋白的排泄,减轻肾组织炎症反应,改善肾脏组织病变,对糖尿病肾脏损伤具有显著且更全面的治疗作用.     

Microalbuminuria in very old patients

In this study, we examined the prevalence and the amount of microalbuminuria in 59 very old subjects above 80 years (study group) and in age-matched subgroups of hypertensive (n=12) and non-insulin dependent diabetic (n=12) patients. In the study group, patients admitted with medical disorders other than renal, cardiovascular or malignant were included. Microalbuminuria was defined as urinary excretion of albumin in 24 h samples above 30 mg/24 h. Mean values for albumin excretion were 21.5±34.5 mg/24 h in the study group, 49.4±78.0 mg/24 h in the hypertension and 23.7±30.6 mg/24 h in the diabetic group (differences not significant). 11 out of 59 people of the study group (18.6%), and 3 out of 12 patients of the hypertension and the diabetes group (25%), respectively, exhibited an elevated albuminuria, indicating that the prevalence of pathological albumin excretion was similar between the three groups. Besides blood pressure, which was only elevated in the hypertension group according to the selection criteria, significant differences in age, serum creatinine or creatinine clearance were not found between the groups. We conclude that microalbuminuria is frequently found in very old patients with a prevalence of 18–25% and that risk factors such as hypertension or diabetes mellitus do not further enhance the high prevalence of albuminuria in the high age.     

Development of diabetic complications in a new diabetic strain of rat (WBN/Kob).

The development of ocular, renal, and neural lesions was examined in male diabetic WBN/Kob rats with endoexocrine pancreatic insufficiency. As for the ocular lesions, around 15 months of age, opacity of the lens began to appear. Opacity was first observed in the periphery of the lens, and then increased rapidly in severity, extending concentrically and centripetally, until total cataracts developed. The incidence of cataracts in male rats was gradually increased and reached almost 100% at 24 months of age. As for renal lesions, the 24-h urinary total protein began to increase at about 13 months of age and reached 50-300 mg/24 h at 13-28 month of age, which was significantly higher than in age-matched male Wistar rats (15-25 mg/24 h). Electrophoretic analysis revealed that the urinary protein was almost all albumin. Morphologically, an increased GBM thickness and glomeruli with segmental or global enlargement of mesangial areas were observed. As for neural lesions, a reduction in motor nerve conduction velocity was demonstrated electrophysiologically, and a marked decrease in density and diameter of myelinated fibers in the sciatic nerves were observed morphometrically. In conclusion, the WBN/Kob rat strain with slowly developing but severe lesions associated with pancreatopathy presents a suitable model for human diabetic complications.     

Urinary albumin excretion is associated with nocturnal systolic blood pressure in resistant hypertensives

Microalbuminuria is a known marker of subclinical organ damage. Its prevalence is higher in patients with resistant hypertension than in subjects with blood pressure at goal. On the other hand, some patients with apparently well-controlled hypertension still have microalbuminuria. The current study aimed to determine the relationship between microalbuminuria and both office and 24-hour ambulatory blood pressure. A cohort of 356 patients (mean age 64 ± 11 years; 40.2% females) with resistant hypertension (blood pressure ≥ 140 and/or 90 mm Hg despite treatment with ≥ 3 drugs, diuretic included) were selected from Spanish hypertension units. Patients with estimated glomerular filtration rate <30 mL/min/1.73 m(2) were excluded. All patients underwent clinical and demographic evaluation, complete laboratory analyses, and good technical-quality 24-hour ambulatory blood pressure monitoring. Urinary albumin/creatinine ratio was averaged from 3 first-morning void urine samples. Microalbuminuria (urinary albumin/creatinine ratio ≥ 2.5 mg/mmol in males or ≥ 3.5 mg/mmol in females) was detected in 46.6%, and impaired renal function (estimated glomerular filtration rate <60 mL/min/1.73 m(2)) was detected in 26.8%. Bivariate analyses showed significant associations of microalbuminuria with older age, reduced estimated glomerular filtration rate, increased nighttime systolic blood pressure, and elevated daytime, nighttime, and 24-hour diastolic blood pressure. In a logistic regression analysis, after age and sex adjustment, elevated nighttime systolic blood pressure (multivariate odds ratio, 1.014 [95% CI, 1.001 to 1.026]; P=0.029) and reduced estimated glomerular filtration rate (multivariate odds ratio, 2.79 [95% CI, 1.57 to 4.96]; P=0.0005) were independently associated with the presence of microalbuminuria. We conclude that microalbuminuria is better associated with increased nighttime systolic blood pressure than with any other office and 24-hour ambulatory blood pressure monitoring parameters.