Progression of nephropathy in type 2 diabetic patients

BACKGROUND: Nephropathy in type 2 diabetes is the single most common cause of end-stage renal disease (ESRD), but the decline in kidney function varies considerably between individuals, and determinants of renal function loss, early in the course of renal disease, have not been clearly identified. METHODS: In a prospective observational study, we followed 227 (60 female) Caucasian type 2 diabetic patients with nephropathy for 6.5 (range 3 to 17) years from a baseline glomerular filtration rate (GFR) of 83 (SD30) mL/min/1.73m(2) with 7 (range 3 to 22) measurements of GFR ((51)Cr-EDTA) per patient. We evaluated determinants of (1) rate of decline in GFR, (2) risk of doubling in serum creatinine or ESRD, and (3) mortality using potential risk factors at baseline and during follow-up. RESULTS: The mean (SD) rate of decline in GFR was 5.2 (4.1) mL/min/year. In multivariate regression analysis, higher baseline albuminuria, systolic blood pressure (SBP), hemoglobin A1c, GFR, age, and degree of diabetic retinopathy were significantly associated with increased rate of decline in GFR (R(2) (adj) 0.24). During follow-up, elevated mean albuminuria, SBP, hemoglobin A1c, and lower hemoglobin, heavy smoking, and presence of diabetic retinopathy were significantly associated with increased decline in GFR (R(2) (adj) 0.26). During follow-up, 63 patients had a doubling in serum creatinine or developed ESRD, and 79 patients died, primarily due to cardiovascular disease. In Cox regression analysis, higher baseline albuminuria, hemoglobin A1c, and SBP, together with lower GFR and hemoglobin, were significantly associated with shorter time to doubling of serum creatinine or ESRD. Higher baseline albuminuria, hemoglobin A1c, SBP, and age were significantly associated with increased mortality. CONCLUSION: Our long-term prospective study of type 2 diabetic patients with nephropathy has revealed several modifiable risk factors of enhanced progression in kidney disease and increased mortality.     

Pyridorin in type 2 diabetic nephropathy

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.     

Urinary copper excretion in type 2 diabetic patients with nephropathy

BACKGROUND/AIMS: The aim of this study was to examine the relationship between the degree of urinary copper excretion and stages of diabetic nephropathy. METHODS: Copper, ceruloplasmin and albumin concentrations were measured in serum and urine samples from 41 type 2 diabetic outpatients with different stages of nephropathy and from 10 healthy controls. The copper/albumin and copper/ceruloplasmin ratios in serum and urine were determined. Furthermore, we examined whether free copper ions are dissociated from ceruloplasmin under various pH conditions. RESULTS: Urinary copper concentrations significantly increased only in macroalbuminuric patients. The copper/ceruloplasmin and copper/albumin ratios in urine were consistently greater than those in serum which were not different between patients and healthy controls except the copper/albumin ratio in macroalbuminuric patients. The ratios in urine decreased in parallel with the progression of nephropathy. Copper was found to be released from ceruloplasmin under acidic conditions. CONCLUSION: Urinary copper excretion in healthy controls may be the result of dissociation from the albumin-copper complex of serum during its passage through the kidney. In diabetic patients with advanced nephropathy, urinary copper excretion may be due to dissociations from both copper-albumin and ceruloplasmin-copper complexes filtered through the damaged glomerulus. Overloading of urinary copper to damaged renal tubules may play some roles in the progression of nephropathy in patients with advanced nephropathy.     

2型糖尿病患者心率变异度与糖尿病肾病的关系

尿微量白蛋白(microalbuminuria，MAU)和心率变异度(heart rate variability，HRV)目前被公认是检出糖尿病肾病(DN)和糖尿病心脏自主神经病变最敏感的指标。我们采用24h动态心电图对糖尿病患者进行HRV的测定．以探讨自主神经病变对DN的影响。     

Population-based assessment of familial clustering of diabetic nephropathy in type 1 diabetes

We determined the magnitude of familial aggregation in the development of diabetic nephropathy (DN) among a population-based cohort of Finnish type 1 diabetic patients. Probands with type 1 diabetes were identified from the nationwide register of all Finnish cases diagnosed during 1965-1979. By 1998, there were 537 families with at least two siblings with type 1 diabetes. These 537 probands and their 616 diabetic siblings were followed for a diagnosis of DN until the end of 2001. We identified 323 cases of DN in these families. If the proband had DN, 38% of the siblings also had DN, whereas out of the diabetic siblings of the probands without DN, only 17% had DN (P = 0.001). Diabetic siblings of the nephropathic probands had a 2.3 times (95% CI 1.4-2.7) higher risk of DN compared with siblings of probands free of DN. The presence of a severe form of DN in the proband increases the risk threefold for diabetic siblings. Sex, the DN of the proband, the age at the onset of diabetes, and parental type 2 diabetes were significant predictors of DN among diabetic siblings. Although the majority of sibpairs with type 1 diabetes are discordant for DN, its presence in one sibling doubles the risk for the other diabetic siblings.     

Decrease in toe pinch force in male type 2 diabetic patients with diabetic nephropathy

Background

The purpose of this cross-sectional study was to investigate the toe pinch force (TPF) of type 2 diabetic patients with diabetic nephropathy by disease stage, and to clarify the factors affecting the TPF.

Methods

Seventy-four men with diabetic nephropathy (age: 62.7?±?8.9 years, duration of diabetes: 14.2?±?8.6 years) were enrolled. According to the staging of diabetic nephropathy, TPF and knee extension force (KEF) were compared among three groups: normoalbuminuria, microalbuminuria, and overt nephropathy. In addition, we investigated factors influencing TPF and KEF by performing multiple regression analysis.

Results

Normoalbuminuria group, microalbuminuria group, and overt nephropathy group included 26, 25, and 23 patients, respectively. The TPF of the overt nephropathy group (3.15?±?0.75 kg) was significantly lower than that of the normoalbuminuria (4.2?±?0.7 kg, p?<?0.001) and microalbuminuria groups (3.65?±?0.81 kg, p?=?0.022). The KEF of the overt nephropathy group (37.1?±?8.3 kgf) was significantly lower than that of the normoalbuminuria group (44.8?±?8.3 kgf, p?=?0.010). Multiple regression analysis revealed that diabetic polyneuropathy (DPN) and diabetic nephropathy were determinant factors of the TPF; and age, body mass index, and diabetic nephropathy were determinant factors of the KEF.

Conclusion

We found in male patients with diabetic nephropathy, the TPF and KEF decreased with progression of diabetic nephropathy. Furthermore, our findings suggest diabetic nephropathy and DPN are critically involved in the reduction of TPF and KEF.

     

Oxidative stress markers in type 2 diabetes patients with diabetic nephropathy

Background

Epidemiological studies show that 5–40 % of type 2 diabetes (T2DM) patients have diabetic nephropathy, and oxidative stress is one of several underlying mechanisms. We investigated associations between oxidative stress markers and severity of diabetic nephropathy.

Methods

Fifty-nine T2DM patients from the endocrinology outpatient department were included, and their levels of oxidative stress markers were measured. Three groups were determined by their urine albumin-to-creatinine ratio (UACR): group A (UACR < 30 mg/g, n = 22); group B (30 ≤ UACR < 300 mg/g, n = 22); and group C (UACR ≥ 300 mg/g, n = 15).

Results

Vitamin C levels correlated negatively and moderately with serum creatinine (γ = ?0.459, p < 0.001), urine albumin (γ _s = ?0.458, p = 0.001) and UACR (γ _s = ?0.408, p = 0.001), but only weakly with hydroxy-2-deoxyguanosine (8-OHdG) and estimated glomerular filtration rate (eGFR). Vitamin C levels decreased as 8-OHdG, serum creatinine, albumin and UACR increased. T2DM patients with more severe diabetic nephropathy had lower vitamin C levels.

Conclusion

Our results identified several oxidative stress markers that may be clinically important in diabetic nephropathy. Studies with larger sample sizes should be undertaken to confirm these findings.

     

Higher urinary IgM excretion in type 2 diabetic nephropathy compared to type 1 diabetic nephropathy.

BACKGROUND: Proteinuria, due to impairment of the charge- and/or size selectivity of the glomerular capillary wall (GCW) is the earliest clinical evidence of diabetic nephropathy (DN). To study the pathophysiological differences between patients with DN in type 1 diabetes mellitus (type 1 DN) and type 2 diabetes mellitus (type 2 DN), we compared the patterns of urinary proteins of different size and charge in the two entities of diabetic kidney disease. METHODS: Urine concentrations of albumin, IgG2, IgG4 and IgM were assessed in 22 (15 males and 7 females) patients with type 1 DN, and in 20 (18 males and 2 females) patients with type 2 DN. Comparisons with one control group of 13 (12 males and one female) patients with nephrosclerosis due to systemic hypertension and a second control group of 16 (14 males and 2 females) healthy controls were made. RESULTS: The urine excretion of IgG2 and IgM and the ratio of IgG2 to IgG4 (IgG2/IgG4), were significantly higher in type 2 DN compared to type 1 DN (P < 0.01). Patients with type 2 DN and patients with nephrosclerosis had significantly higher urine excretion of IgG and IgM compared to the age-matched healthy subjects (P < 0.001). The IgG2/IgG4 ratio was higher in type 2 DN compared to nephrosclerosis and healthy controls (P < 0.01). CONCLUSION: The increased urine excretion of IgG and IgM that accompanies albuminuria in type 2 DN suggests that the dominant pathophysiological mechanism of proteinuria in type 2 DN might be an alteration of the size selective properties of the glomerular capillary wall, including the occurrence of non-discriminatory "shunt pathways." The charge selective properties of the glomerular capillary wall seem to be intact in type 2 DN, as indicated by the high IgG2/IgG4 ratio. The mechanisms of proteinuria in type 1 DN seem to be merely a consequence of an impaired charge selectivity of the glomerular capillary wall.     

Familial clustering and immunogenetic aspects of IgA nephropathy

IgA nephropathy (IgAN) has been assumed to develop sporadically in individuals. We review the recent clinical and laboratory evidence that supports a genetic influence in the immunopathogenesis in some patients. These data include (1) families with multiple members with the disease not sharing a known nephrotoxic factor, (2) clustering of the birthplaces of ancestors of large pedigrees with multiple affected members, suggesting a "founder effect," (3) DNA alleles and protein phenotypes associated with IgAN (or a clinical subset) in some patient populations or that cosegregate with the disease in families with multiple affected members, and (4) immunologic abnormalities of patients shared by relatives with renal disease. However, the lack of understanding the fundamental pathogenetic mechanisms hinders progress in the pursuit of genetically controlled process in this disease. Furthermore, the diagnosis requires a renal biopsy, and no therapy has been proven effective. Therefore, asymptomatic family members with IgAN may forego the invasive diagnostic procedure necessary to establish the diagnosis, and instances of familial disease may not be investigated. Nonetheless, the increasing awareness of families with multiple affected members offers an opportunity to investigate the hypothesized genetic influence in the pathogenesis of IgAN.     

Urinary albumin as an indicator of diabetic nephropathy lesions in Japanese type 2 diabetic patients

Caucasian type 2 diabetic patients with microalbuminuria (MA) or overt nephropathy (ON) show greater heterogeneity of renal lesions than type 1 diabetic patients. We examined whether a similar situation exists in 30 Japanese type 2 diabetic patients [21 male, age 48 +/- (SD) 8 years, known duration 11 +/- (SD) 8 years] without definable renal disease other than diabetic nephropathy. Six patients were normoalbuminuric (NA), 11 MA, and 13 had ON. Normal controls were 9 age-matched Japanese living-related renal transplant donors. Electron microscopic morphometry was performed on renal biopsy specimens and related to renal function. Glomerular basement membrane width and mesangial fractional volume [Vv(Mes/glom)] were increased in all type 2 diabetic patients groups (NA, MA, ON) as compared with normal controls. The Vv(Mes/glom) correlated directly with urinary albumin/creatinine. However, Vv(Mes/glom) as well as glomerular basement membrane width overlapped among the three functional categories (NA, MA, ON) and normal controls. In conclusion: (1) similar to Caucasian type 2 diabetic patients, Japanese type 2 diabetic patients have greater heterogeneity of renal structure than Caucasian type 1 diabetic patients, and (2) urinary albumin is not a reliable indicator of underlying renal structure in Japanese type 2 diabetic patients.     

How to predict nephropathy in type 1 diabetic patients

OBJECTIVE: Do exaggerated increases in blood pressure and albuminuria during exercise occur earlier than microalbuminuria and which type of test is most predictive of diabetic nephropathy? MATERIAL AND METHODS: A total of 33 insulin-dependent normoalbuminuric men (mean duration of diabetes 14 years; mean age 28 years) and 34 age-matched apparently healthy control subjects were studied. Urinary albumin excretion, heart rate and blood pressure were measured during fixed workload (150 W) and fixed heart rate (155 beats/min) tests. Mean follow-up time was 13.1 +/- 3.2 years. A urinary albumin level in early-morning urine persistently >30 mg/l was considered a sign of diabetic nephropathy. RESULTS: Sixteen patients reached the endpoints of the study. Eleven had developed microalbuminuria and five macroalbuminuria (persistent levels of urinary albumin >300 mg/l). Of the latter patients, two needed dialysis. Systolic blood pressure and albumin excretion during the fixed heart rate test were higher in diabetic patients who developed signs of nephropathy than in control subjects and diabetic subjects with persistent healthy kidneys. Such differences were not found in the fixed workload test. There were no differences in glycated haemoglobin, blood pressure levels or albumin excretion at baseline between the two diabetic groups. CONCLUSIONS: To predict the development of diabetic nephropathy it seems important to choose a fixed heart rate test. High levels of systolic blood pressure in such a test were associated with the development of micro- and macroalbuminuria.     

2型糖尿病肾病危险因素

在最近10年中,糖尿病终末期肾病(ESRD)的发病率和患病率逐年增长。我们通过比较及多因素分析方法,探讨了与2型糖尿病肾病发病有关的各种危险因素。一、对象和方法 1．对象:我院1999年1月1日至2002年3月31日住院患者按WHO诊断标准诊断为2型糖尿病者共692     

Improvement of renal function in type 2 diabetic nephropathy

BACKGROUND: Therapeutic failure in preventing renal disease progression in type 2 diabetic nephropathy (DN) is due to a failure in the early detection of DN by microalbuminuria and the inappropriate correction of renal hemodynamic maladjustment secondary to glomerular endothelial dysfunction. METHODS: Thirty patients associated with normoalbuminuric type 2 DN were subject to the following studies: tubular function by means of fractional excretion of magnesium (FE Mg), vascular function by means of determining the circulating endothelial cell, VEGF, VEGF/TGF B ratio, and intrarenal hemodynamic studies. RESULTS: FE Mg, circulating endothelial cells, and TGF B were abnormally elevated, and VEGF/TGF B ratio was decreased in these normoalbuminuric patients. The intrarenal hemodynamic study revealed a hemodynamic maladjustment characterized by a preferential constriction at the efferent arteriole and a reduction in peritubular capillary flow. Following treatment with vasodilators, a decrease in efferent arteriolar resistance and increase in peritubular capillary flow as well as glomerular clearance were observed. CONCLUSION: FE Mg appears to be a more sensitive marker than microalbuminuria for the early detection of DN. Increased endothelial cell injury is reflected by enhanced circulating endothelial cell loss in conjunction with the increased TGF B and the decreased ratio between VEGF and TGF B. This is further supported by the dysfunctioning glomerular endothelium, which is characterized by hemodynamic maladjustment and a reduction in the peritubular capillary flow. A correction of such hemodynamic maladjustment by multidrug vasodilators effectively improves renal perfusion and restores renal function in type 2 DN.     

ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy

Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.     

西藏地区糖尿病肾病临床特点分析

目的 分析西藏地区2型糖尿病肾病(DN)的临床特点。 方法 回顾分析2001年5月至2006年10月间在我科住院的306例2型糖尿病（DM）患者的临床资料。 结果 306例DM患者包括151例DN和155例非DN患者，根据尿白蛋白及Scr水平，DN组患者再分为微量白蛋白尿组、临床蛋白尿组和肾功能不全组。DN组尿微量白蛋白、Scr和血、尿β2微球蛋白(MG)均较非DN组显著增高（均P < 0.01）；且尿微量白蛋白与收缩压、血β2-MG呈正相关（r = 0.187， P < 0.05； r = 0.297， P < 0.01），而与GFR呈负相关（r = －0.287，P < 0.01）。DN组高血压发生率高（60.27％），血压显著高于非DN组（P < 0.01），且以收缩压更显著。DN组发生尿毒症者14例（9.27％），死亡8例（5.30％），其中5例死于尿毒症；并发糖尿病视网膜病变20例(13.25%)；发生心脑血管意外者6例(3.97%)。 结论 西藏地区2型糖尿病肾病早期即有明显的蛋白尿、血压及血、尿β2-MG增高，后期GFR急剧下降且并发症多而严重。     

葛根素对2型糖尿病肾病的疗效

我院肾内科采用注射用葛根素为主中西医结合方法治疗Ⅳ期2型糖尿病肾病42例,并与单用西药常规治疗的38例对照,报告如下. 一、对象与方法 1.对象:选择2009年1月至2010年4月在我院住院的2型糖尿病临床肾病期患者80例,诊断据Mogensen分期标准.症状不典型或诊断有疑问时行肾组织活检,证实有肾小球结节性硬化及弥漫性肾小球硬化.患者按数字表法随机分为2组,即葛根素组和对照组,2组的性别、年龄、病程、体质量指数(BMI)、血压等差异均无统计学意义,具有可比性.     

Higher frequency of apolipoprotein E2 allele in type 2 diabetic patients with nephropathy in Taiwan

BACKGROUND: Diabetes is one of the major causes of end stage renal failure in Taiwan. Previous studies have indicated that lipid abnormalities might contribute to the development and progression of diabetic nephropathy (DN). Apolipoprotein E (apo E) regulates the metabolism of lipoproteins. Three different apo E alleles (epsilon2, epsilon3 and epsilon4) produce apo E isoproteins, apo E2, apo E3 and apo E4. Thus, the apo E gene polymorphism may be associated with DN. METHODS: To investigate the distribution of apo E genotype in type 2 diabetic Taiwanese, we examined 314 patients with type 2 diabetes (100 without nephropathy and 214 with nephropathy) and 150 age-matched normal controls. The diagnosis of nephropathy was made when daily protein loss exceeded 500 mg. The apo E gene polymorphism was analyzed by polymerase chain reaction. RESULTS: Our study found that the frequency of apo E2 allele was significantly higher in the diabetics with nephropathy- non-dialysis group (7.7%) and diabetics with nephropathy- dialysis group (7.7%) than in normal controls (1.7%) (p < 0.001) and diabetics without nephropathy (2.0%) (p < 0.01). The E3 and E4 allele frequencies were not significantly different among groups. CONCLUSION: These findings imply that apo E polymorphism is apparently related to the development of DN in type 2 diabetes in Taiwan.     

2型糖尿病肾病和糖尿病性视网膜病变的相关性研究

目的探讨2型糖尿病肾病和糖尿病性视网膜病变的发病机制及其两者之间的相关性。方法选择2004年1月至2014年12月北京中日友好医院肾内科经肾穿刺活检确诊的2型糖尿病肾病(diabetic nephropathy,DN)患者95例,按照肾脏病理改变程度分为5组,即DNⅠ组10例,DNⅡa组12例,DNⅡb组16例,DNⅢ组54例,DNⅣ组3例;将不同组间视网膜病变进行比较,分析视网膜病变与肾脏损伤之间的关系,以及视网膜病变与常用临床指标[24 h尿蛋白定量、空腹血糖(fasting blood glucose,FBG)、糖化血红蛋白(glycosylated hemoglobin,HbA1c)、血肌酐(SCr)及肌酐清除率(creatinine clearance rate,Ccr)]之间的关系。结果 DN患者肾脏损伤病理分型与视网膜病变呈正相关(r=0.458,P=0.016),但仍有23.2%患者无视网膜病变,分别发生在80.00%的DNⅠ组、33.33%的DNⅡa组、12.50%的DNⅡb组、14.81%的DNⅢ组患者中。临床指标中仅24 h尿蛋白定量与糖尿病视网膜病变的发生和发展相关。结论尽管糖尿病性视网膜病变常被提示DN,但少部分DN不存在视网膜病变的情况也应被重视。     

Polymorphisms in the nephrin gene and diabetic nephropathy in type 1 diabetic patients

BACKGROUND: Several mutations in the nephrin gene are responsible for the lack of slit membrane of the glomeruli leading to massive proteinuria present already in utero. Variations in the nephrin gene may also affect the degree of proteinuria in acquired kidney diseases. We tested the hypothesis of whether any of the polymorphisms identified in the coding region of the nephrin gene were associated with diabetic nephropathy. METHODS: In a case-control, cross-sectional study, 996 Finnish type 1 diabetic patients from the FinnDiane Study were genotyped by standard polymerase chain reaction protocol. RESULTS: The frequencies of the rare alleles in the E117K, R408Q, and N1077S polymorphisms in the entire cohort were 34%, 8%, and 12%, respectively. When comparing patients with a mutant allele with the wild genotype there was no difference between the patients with end-stage renal disease, proteinuria, microalbuminuria, and those with a normal albumin excretion rate (df =3, chi2 =1.62, 1.31 and 0.77). Neither were the polymorphisms associated with the progression of kidney disease, nor with creatinine clearance and albumin excretion rate. CONCLUSION: This study does not support an involvement of the coding region of the nephrin gene in the pathogenesis of diabetic nephropathy in type 1 diabetic patients.