Renal arteriolar hyalinosis, not intimal thickening in large arteries, is associated with cardiovascular events in people with biopsy-proven diabetic nephropathy.

AIMS: Diabetic nephropathy, a pathologically diagnosed microvascular complication of diabetes, is a strong risk factor for cardiovascular events, which mainly involve arteries larger than those affected in diabetic nephropathy. However, the association between diabetic nephropathy pathological findings and cardiovascular events has not been well studied. We aimed to investigate whether the pathological findings in diabetic nephropathy are closely associated with cardiovascular event development. METHODS: This retrospective cohort study analysed 377 people with type 2 diabetes and biopsy-proven diabetic nephropathy, with a median follow-up of 5.9 years (interquartile range 2.0 to 13.5). We investigated how cardiovascular events were impacted by two vascular diabetic nephropathy lesions, namely arteriolar hyalinosis and arterial intimal thickening, and by glomerular and interstitial lesions. RESULTS: Of the 377 people with diabetic nephropathy, 331 (88%) and 295 (78%) had arteriolar hyalinosis and arterial intimal thickening, respectively. During the entire follow-up period, those with arteriolar hyalinosis had higher cardiovascular event rates in the crude Kaplan-Meier analysis than those without these lesions (P = 0.005, log-rank test). When fully adjusted for clinically relevant confounders, arteriolar hyalinosis independently predicted cardiovascular events [hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.12, 3.86], but we did not find any relationship between arterial intimal thickening and cardiovascular events (HR 0.89; 95% CI 0.60, 1.37). Additionally, neither glomerular nor interstitial lesions were independently associated with cardiovascular events in the fully adjusted model. CONCLUSIONS: Arteriolar hyalinosis, but not intimal thickening of large arteries, was strongly associated with cardiovascular events in people with diabetic nephropathy.

Frailty, health-related quality of life and mental well-being in older adults with cardiometabolic risk factors.

OBJECTIVE: Frailty is an emergent health-related problem in older adults. The aim of this study was to examine the health-related quality of life (HRQOL) and the effect of frailty in elderly patients with cardiometabolic risk factors. METHODS: One-hundred and one patients 65 years or older responded to an HRQOL assessment using the World Health Organization Quality of Life (WHOQOL)-26 questionnaire. Frailty was assessed using two indices: the Hebrew Rehabilitation Center for Aged (HRCA) vulnerability index and the Vulnerable Elders Survey (VES) index. In addition, these patients completed self-rating questionnaires assessing mental well-being [the 28-item version of the General Health Questionnaire (GHQ-28)] and depression (Geriatric Depression Scale). RESULTS: Based on the combination of HRCA and VES indices, 24 subjects (23.7%) met the criteria of frail. Persons > or = 75 years old and those with depressive mood or lower creatinine clearance had significantly lower WHOQOL-26 scores than their counterparts. Diabetes and macrovascular complications did not associate with the WHOQOL-26 scores. Compared with non-frail patients, the frail scored lower on the WHOQOL-26 questionnaire after adjusting for age, kidney dysfunction and depressive mood. Frail patients also reported significantly higher the GHQ-28 scores compared with non-frail patients. CONCLUSIONS: Frail older adults had a significant lower HRQOL, as well as lower mental well-being, independent of age, diabetes, macrovascular complication, kidney dysfunction and depressed mood.

Advanced glycation end products in nondiabetic patients with coronary artery disease.

OBJECTIVE: To investigate whether advanced glycation end products (AGEs) participate in the development of coronary artery disease (CAD) in nondiabetic and diabetic subjects. RESEARCH DESIGN AND METHODS: Serum concentrations of AGEs were measured using a newly established enzyme-linked immunosorbent assay in 48 nondiabetic patients (normal glucose tolerance, n = 20; impaired glucose tolerance, n = 28) who received coronary angiography for the study of chest pain or suspected CAD. Insulin sensitivity was examined by the euglycemic-hyperinsulinemic glucose clamp technique and was estimated as the mean glucose infusion rate during the last 30 min of clamp time (M value). RESULTS: Patients were classified into four groups based on the number of significantly stenosed vessels, defined as 0-, 1-, 2-, or 3-vessel disease. Serum concentrations of AGEs were significantly higher in nondiabetic subjects with CAD than in control subjects (2.42 +/- 0.65 vs. 1.96 +/- 0.40 mU/ml, P < 0.01) and significantly correlated with the number of significantly stenosed vessels (r = 0.678, P < 0.001). M values significantly inversely correlated with serum concentrations of AGEs (r = -0.490, P < 0.05). In multiple regression analysis, with the number of significantly stenosed vessels as the dependent variable, serum concentrations of AGEs, 2-h plasma glucose, and areas under the plasma glucose response curve were independently associated. CONCLUSIONS: This pilot study indicates the relation between AGEs and the severity of CAD in nondiabetic patients. The measurement of serum AGE concentrations may be predictive of vascular damage.

Association of transforming growth factor-beta1 T29C polymorphism with the progression of diabetic nephropathy.

Diabetes mellitus is a leading cause of end-stage renal disease in the Western world. Histologically, mesangial expansion with increased extracellular matrix protein is observed in patients with diabetic nephropathy. Because transforming growth factor (TGF)-beta promotes extracellular matrix production in response to high glucose, TGF-beta is considered to play a central role in the pathogenesis of diabetic nephropathy. We investigated the association of TGF-beta1 T29C polymorphism and the progression of diabetic nephropathy. Forty patients with type 2 diabetes mellitus were enrolled. All patients had had diabetes for more than 10 years. DNA was extracted from peripheral blood cells, and genotype was determined using real-time polymerase chain reaction method. Patients were classified into three groups according to genotype: TT, TC, and CC. Grade of diabetic nephropathy was determined using the amount of urinary excretion of albumin. Demographic characteristics of the patients with each genotype were not statistically different. No differences in the glycemic control and the mode of therapy were observed. Among patients with three genotypes, the severity of diabetic nephropathy was not statistically different. The patients with TT genotype tended to have a higher rate of progression of nephropathy; however, no statistically significant difference was observed among the three groups. Our results suggest that TGF-beta1 T29C polymorphism is not associated with the progression of diabetic nephropathy. Further studies are required to determine the exact role of this polymorphism in the progression of diabetic nephropathy.

Use of novel assays to indicate that O-esters and S-esters are produced by the same enzyme in brewing yeast.

Ethanol- and methanethiol-dependent removal of acetyl-CoA by crude extracts of ale yeast has been monitored using a decrease in OD232. Activity has also been detected in these extracts after fractionation on polyacrylamide gels, in this case using a novel assay in which the coenzyme A produced in the reaction is linked via DCPIP reduction to color formation from nitroblue tetrazolium. Ethanol- and methanethiol-dependent activities migrate identically on such gels, and only one band of color formation was observed. Furthermore they displayed closely similar sensitivity to heating at 40 degrees C and 60 degrees C and pH optima, with activity maximal at pH 7.5. It is likely that a single enzyme is responsible for the formation of O-esters and S-esters in yeast. Initial kinetic studies indicate that methanethiol has higher affinity for the enzyme than has ethanol and a higher maximum velocity. However, the enzyme has a much lower Km for acetyl-CoA, suggesting that the alcohol or thiol substrate is the more likely substrate to be limiting.

Serum IgA levels in patients with diabetic nephropathy and IgA nephropathy superimposed on diabetes mellitus.

The aim of this study was to examine the relationship between serum immunoglobulin A (IgA) levels and diabetic nephropathy in patients with type 2 diabetes mellitus, and to describe the role of IgA nephropathy superimposed on diabetes mellitus. A total of 127 type 2 diabetic patients were studied. Of these diabetics, 74 had no proteinuria, 35 had diabetic glomerulosclerosis confirmed by renal biopsy, 13 had superimposed IgA nephropathy, and five had superimposed non-IgA nephropathy. We also studied 93 non-diabetic patients with IgA nephropathy, 24 non-diabetic patients with non-IgA nephropathy, and 38 non-diabetic controls. Serum IgA levels were significantly higher in IgA nephropathy patients (350+/-130 mg/dl) than in non-diabetic controls (228+/-56 mg/dl) and diabetics without proteinuria (268+/-104 mg/dl). Serum IgA levels were also significantly higher in diabetics with superimposed IgA nephropathy (470+/-208 mg/dl) than in non-diabetic controls, non-IgA nephropathy patients (270+/-133 mg/dl), diabetics without proteinuria, diabetic glomerulosclerosis alone (302+/-126 mg/dl), and diabetics with superimposed non-IgA nephropathy (248+/-137 mg/dl). The prevalence of high serum IgA levels was significantly higher in diabetics with superimposed IgA nephropathy (76.9%) than in diabetic glomerulosclerosis alone (31.4%) and diabetics with superimposed non-IgA nephropathy (25.0%). In conclusion, our findings indicate that high serum IgA level is a sign of the existence of IgA nephropathy superimposed on diabetes mellitus.

Association of Chlamydia pneumoniae infection with diabetic nephropathy.

We evaluated the association of Chlamydia pneumoniae (CP) infection with progression of diabetic nephropathy. Type 2 diabetic patients (60) were divided into two groups, those with incipient nephropathy and those with advanced nephropathy, based on the severity of diffuse glomerular lesions using Gellman's criteria. Type 2 (34) diabetic patients without nephropathy (normoalbuminuria) and 59 nondiabetics served as control groups. Serum IgG-antibody against CP was measured using ELISA. CP antibody was detected in 45.8% of nondiabetic controls, in 47.1% of diabetic patients without nephropathy, in 52.6% of diabetic patients with incipient nephropathy, and 78% of diabetic patients with advanced nephropathy. There was 4.22-fold increase in the risk of advanced nephropathy associated with the presence of CP antibody. Our findings indicate an association between chronic CP infection and advanced diabetic nephropathy.

Clinical and morphological predictors of renal outcome in adult patients with focal and segmental glomerulosclerosis (FSGS).

In this retrospective study, we examined 35 adult patients with biopsy-proven, primary focal and segmental glomerulosclerosis (FSGS) and nephrotic syndrome to determine whether any of the clinical and morphological features of FSGS were associated with a higher risk of a poor renal outcome. Clinical factors assessed were the age, sex, amount of urinary protein, and presence of microscopic hematuria, hypertension and renal dysfunction at onset in each patient. Morphological parameters included the number of segmental sclerosis and global sclerosis, sclerosis score, location of segmental sclerosis, mean glomerular diameter, grade of tubulo-interstitial changes, and presence of vascular lesions. Twenty-three patients (66%) were in complete or incomplete (partial) remission, and 12 (34%) were non-responders at the end of follow-up. On univariate analysis, the age at onset, sclerosis score, mean glomerular diameter, and grade of tubulo-interstitial changes in no response were significantly greater than those parameters in remission. Multivariate logistic regression analysis revealed that the degree of tubulo-interstitial changes and mean glomerular diameter were independent risk factors for a poor renal outcome. These findings suggest that the estimation of these latter two parameters allows the nephrologist to predict the probable course and prognosis of an adult with FSGS. Intensive and prolonged therapy is recommended for patients without these two morphological features.

Growth of Trichoderma viride on crude cell wall preparations from barley.

Trichoderma viride can utilize crude cell wall preparations from barley starchy endosperm as sole source of carbon and energy. In the process beta-(1-->3)(1-->4)-glucan and arabinoxylan are released. The onset of release of the latter preceded that of glucan, consistent with arabinoxylan being encountered and utilized first. The release of several enzymes was observed during growth of Trichoderma on this substrate: endo-beta-(1-->3)(1-->4)-glucanase, endo-beta-(1-->4)-glucanase, endo-xylanase, arabinofuranosidase, esterase, carboxypeptidase, and "beta-glucan solubilase". It is inferred that each of these activities is necessary for the digestion of this substrate.

Glomerular lesions in patients with non-insulin-dependent diabetes mellitus and microalbuminuria.

To evaluate the renal structural changes in non-insulin-dependent diabetes mellitus (NIDDM), we studied the renal histological findings and urinary albumin excretion in 75 patients with NIDDM. They were divided into two groups according to excretion of urinary albumin: 40 cases of normoalbuminuria and 35 cases of microalbuminuria. Renal biopsy specimens were evaluated by light microscopy. Diffuse glomerular lesions were graded on a scale of D0 through DIV (Gellman's criteria). The incidence of microalbuminuria was 19.2% in D0, 53.3% in DI, 61.5% in DII and 100% in DIII. Grade IV lesions were not present in either group. Creatinine clearance differed significantly between the groups with and without microalbuminuria. There was no difference between the groups with normoalbuminuria and microalbuminuria in the incidence of retinopathy and hypertension, or in the urinary excretion of beta 2MG and NAG. We conclude that microalbuminuria in NIDDM indicates the early morphological changes of glomerular lesions.

Henoch-Schönlein purpura nephritis associated with polycythemia vera.

We present a 53-year-old man with rapidly progressive glomerulonephritis and Henoch-Schönlein purpura which developed during the course of treatment for polycythemia vera. An initial renal biopsy specimen showed mesangial proliferative glomerulonephritis. The patient was admitted to the hospital with cutaneous purpura and progressive renal failure after having received 700 mg of ranimustine over a 29 month period as therapy for the polycythemia vera. A second renal biopsy specimen revealed crescentic glomerulonephritis with deposition of immunofluorescent IgA. These data suggest that Henoch-Schönlein purpura nephritis may occur in response to ranimustine therapy.

Diagnostic significance of urinary fibronectin in diabetic nephropathy.

We evaluated the diagnostic utility of urinary fibronectin (FN) in patients with diabetic nephropathy by comparing the findings with those of renal biopsy specimens. A total of 46 diabetic patients were divided into four groups, D0, DI, DII and DIII-IV, according to the severity of diffuse glomerular lesions using Gellman's criteria. Using 24-hour urine specimens, FN was measured by a solid phase enzyme-linked immunosorbent assay. The urinary excretion of FN was significantly higher in the overt proteinuric group than in the normo- and micro-albuminuric groups. Urinary FN level showed a significant increase with respect to the progress of glomerular diffuse lesions. There was a weak correlation between the urinary level of FN and serum creatinine level and a weak inverse correlation between the urinary level of FN and creatinine clearance. When patients with overt proteinuria were excluded from the analysis, there was no correlation between the urinary level of FN and serum creatinine level, creatinine clearance, or that of beta 2-microglobulin and NAG. The findings indicate that urinary FN may be useful in estimating pathologic conditions, especially the early stage of diabetic nephropathy.

[Progressive course of nephropathy with non-insulin-dependent diabetes mellitus--structural-functional relationship].

We studied quantitatively a morphological change in diabetic nephropathy by light microscopy. The renal biopsy specimens were examined using color image processor in 53 patients with non-insulin-dependent diabetes mellitus (NIDDM). These patients, aged 22 to 69 years, had been NIDDM for 2 months to 27 years. Glomerular area (GA), mesangial rate (MR) and length of capillary filtration (CFL) were used as the morphological parameters. Duration of diabetes, urinary albumin excretion and creatinine clearance (Ccr) were chosen as clinical manifestations. Duration of diabetes was correlated with MR (r = 0.55, p < 0.01), but not GA. Glomerular hypertrophy could not be found. A significant relationship between Ccr and CFL were noticed (r = 0.64, p < 0.01).

Diagnostic significance of urinary transferrin in diabetic nephropathy.

We evaluated the diagnostic utility of urinary transferrin (Tf) in patients with diabetic nephropathy by comparing the diagnostic findings with those of clinical stage and renal biopsy specimens. According to the rate of urinary albumin excretion, a total of 60 patients with non-insulin-dependent diabetes mellitus were separated into normoalbuminuria (< 28.8 mg/day), microalbuminuria (28.8 approximately 288 mg/day), and overt proteinuria (> 288 mg/day). They were also divided into 5 groups, D0, DI, DII, DIII and DIV according to the severity of glomerular diffuse lesions using Gellman's criteria. Thirty-eight non-diabetic volunteers were used as controls. Using 24-hour urine specimens, Tf was measured by latex-immuno-turbidimetry. Urinary concentrations of albumin, alpha 1-microglobulin, beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) were also evaluated. Urinary Tf was significantly increased in the diabetic patients relative to the non-diabetic controls. The incidence of microtransferrinuria (440 approximately 4,400 micrograms/day) was 33.3% in normoalbuminuria, 63.2% in microalbuminuria, and 18.2% in overt proteinuria. The incidence of overt transferrinuria (> 4,400 micrograms/day) was 0%, 36.8% and 81.8%, respectively. Among the diabetic patients, urinary Tf showed a significant increase with respect to the progress of glomerular diffuse lesions. The glomerular diffuse lesions of 10 normoalbuminuric cases with microtransferrinuria were graded as DI in 8 cases, DII in 1 case, and DIII in 1 case. There was a significant correlation between the urinary excretion of Tf and that of albumin, alpha 1-microglobulin or NAG. The findings indicate that urinary Tf may be useful in detecting diabetic nephropathy at an early stage.

Effect of exercise on hemodynamics and urinary protein excretion in patients with early-stage diabetic nephropathy.

We investigated the effects of exercise on hemodynamics and urinary protein excretion in 15 patients with early-stage diabetic nephropathy (DN) as compared the findings with these of 16 healthy volunteers. Patients were divided into two groups according to their renal histopathologic findings; Group D0 consisted of 8 patients in whom light microscopy showed minor glomerular abnormalities and Group DI consisted of 7 patients with early stage diffuse lesions. The subjects exercised on a treadmill at a workload of 4.7 METS for 20 minutes. Systolic blood pressure, heart rate and the pressure rate product were significantly higher in the DI group than in the D0 and control groups during exercise. Diastolic blood pressure was similar among the three groups. Creatinine clearance was unchanged during exercise. Urinary albumin excretion, urinary acid soluble protein excretion and urinary alpha 1-microglobulin excretion were all significantly increased in group DI compared with the D0 and control groups. Excretion of beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase activity were unchanged during exercise. Our findings suggest that this provocative exercise test is useful for diagnosing early-stage diabetic nephropathy.

Diagnostic significance of urinary sialic acid in diabetic nephropathy.

The diagnostic significance of urinary sialic acid (SA) determinations was evaluated in relation to the histological findings of renal biopsy specimens. The subjects enrolled in this study comprised 82 diabetics. They were divided into 4 groups according to Gellman's criteria, namely D0, DI, DII and DIII approximately IV. Thirty non-diabetic healthy volunteers were used as controls. The urinary SA was measured by high performance liquid chromatography, and the urinary albumin excretion was estimated by solid phase radioimmunoassay. In addition, urine samples were assayed for N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (beta 2MG). The urinary level of total SA (under conditions of hydrolysis) was significantly increased in the DII and DIII approximately IV groups as compared to the controls; however, a similar value was observed in the D0, DI and control groups. The urinary level of glycoprotein-bound SA was significantly increased in all diabetics as compared to the control group, and was significantly higher in the DII and DIII approximately IV groups than in the D0 and DI groups. The bound-SA/total-SA ratio (B/T ratio) showed a significant increase with respect to the progress of diffuse lesions. A weak correlation was noted between the B/T ratio and urinary protein excretion. However, there was no correlation between the B/T ratio and other indices. The urinary SA is considered to represent a useful indicator for estimating diabetic nephropathy.

Role of tissue inhibitors of metalloproteinase in diabetic nephropathy.

We evaluated the role of tissue inhibitors of metalloproteinase-1 (TIMP-1) in patients with diabetic nephropathy by comparing the serum and urine TIMP-1 levels with those of renal biopsy specimens. A total of 35 diabetic patients were divided into four groups, D0, DI, DII and DIII-IV, according to the severity of diffuse glomerular lesions using Gellman's criteria. Using serum and 24-hour urine specimens, TIMP-1 was measured by a sandwich enzyme immunoassay. Serum and urinary TIMP-1 showed significant increases in association with the progress of glomerular diffuse lesions. There was no correlation between serum TIMP-1 and serum creatinine, creatinine clearance, serum and urinary beta 2-microglobulin, urinary NAG, HbA1c, or urinary TIMP-1. There was a significant correlation between urinary TIMP-1 and urinary albumin, and was a significant correlation between urinary TIMP-1 and urinary NAG. We conclude that TIMP-1 has a potential role in the regulation of glomerular matrix accumulation in diabetic nephropathy.

[Diagnostic significance of urinary immunoglobulin G in diabetic nephropathy].

An early manifestation of diabetic nephropathy, increased excretion of albumin, is now generally believed to be sufficiently specific, particularly in subjects with diabetes mellitus, to predict the subsequent development of clinically overt diabetic nephropathy. However, certain other proteins besides albumin may also be excreted in abnormal amounts during this early phase of diabetic nephropathy. We evaluated the diagnostic utility of urinary immunoglobulin G (IgG) in patients with diabetic nephropathy by comparing the findings with the clinical stage and renal biopsy specimen. Using 24-hour urine samples, IgG was measured by an enzyme-linked immunosorbent assay. In addition, urine samples were assayed for albumin, transferrin, beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase. Serum IgG concentration and HbA1c were also evaluated. A total of 197 patients with non-insulin-dependent diabetes mellitus were enrolled in this study. Subjects were grouped according to the rate of urinary albumin excretion (clinical stage). Fifty of these cases were also divided into four groups according to the severity of diffuse glomerular lesions using Gellman's criteria. The urinary excretion of IgG was significantly increased in diabetic patients as compared with the healthy controls. Among diabetic patients, IgG level showed a significant increase with respect to the clinical stage of nephropathy and the progress of glomerular diffuse lesions. In the stage of normoalbuminuria, the urinary excretion of IgG showed a significant increase in parallel with the progress of glomerular diffuse lesions, whereas there was no relationship between the urinary excretion of albumin and the progress of glomerular diffuse lesions. While the excretion of IgG correlated with that of albumin and transferrin, there was no correlation between the excretion of IgG and the other laboratory indices evaluated. These findings indicate that measurement of urinary IgG may be more useful than albuminuria in detecting the early stage of diabetic nephropathy.

Membranous nephropathy with crescents in rheumatoid arthritis: a case report.

A 59-year-old man with long-standing rheumatoid arthritis (RA) developed renal dysfunction, proteinuria and hematuria. Neither gold nor penicillamine had been given. Light microscopy of a renal biopsy specimen revealed membranous nephropathy with crescents of various stages. The possible pathogenesis of such an unusual combination of membranous nephropathy and crescents in RA is discussed.

[A case of Bartter's syndrome with chronic renal failure due to chronic interstitial nephritis].

We report a case of 45-year-old women with Bartter's syndrome and concomitant renal dysfunction. In 1986, the patient demonstrated muscle weakness and serum potassium levels as low as 1.1 mEq/l. She was suspected of having Bartter's syndrome because of hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normotension. Pretibial edema developed in 1989 for which she received 40 to 100 mg/week of furosemide intermittently for the next 5 years. Her serum potassium level ranged from 1.5 to 3.9 mEq/l. In 1991, her serum creatinine level rose to 2.1 mg/dl, then continued to increase gradually. She was admitted to our hospital in 1994 for evaluation of the renal dysfunction. Decreased creatinine clearance (44 ml/min) and a defect in urinary concentrating capacity (Fishberg's test, 370 mOsm/kg.H2O) were detected. Renal biopsy revealed juxtaglomerular cell hyperplasia. These findings resulted in the diagnosis of Bartter's syndrome. The renal biopsy also showed diffuse interstitial fibrosis and marked tubular atrophy. We postulate in this case that long-term hypokalemia due to Bartter's syndrome and the administration of furosemide led to chronic interstitial nephritis and renal dysfunction.