NPHS2基因多态性与中国北方IgA肾病患者的相关性

目的 分析中国北方地区IgA肾病患者NPHS2基因多态性及其与IgA肾病患者蛋白尿和肾功能的关系。方法 将IgA肾病患者按临床表现分为肾病综合征组和单纯血尿组(各16例)。通过基因测序法筛查与中国北方IgA肾病患者蛋白尿水平相关的NPHS2基因的多态性。根据筛查结果,采用PCR-限制性片段长度多态性技术(PCR-RFLP)检测537例原发性IgA肾病患者NPHS2基因的C357T多态性,比较不同基因型之间临床表现的差异。结果 (1)检测到8种基因多态性：-931A＞T、-601C ＞T、19G＞T、171A＞G、357C＞T、IVS3-21C＞T、1023C＞T和1107A ＞G。(2)上述测序结果提示NPHS2基因357T等位基因频率在肾病综合征组明显低于单纯血尿组(0.038比0.125,P＜0.05),说明此多态性可能和IgA患者发生大量蛋白尿相关。故选择C357T多态性做大样本分析。(3)在537例有临床资料的IgA肾病患者中,比较357CC基因型和357CT/TT基因型的患者在性别、肾穿时年龄、血压、肉眼血尿、蛋白尿、发病时肾功能的差别,结果显示携带NPHS2 357CT/TT 基因型的患者24h尿蛋白定量程度较轻(P =0.023)。与肾病综合征组相比,携带T等位基因的患者蛋白尿小于3.5 g/d的比例明显增多(P=0.017)。多因素logistic回归分析表明NPHS2的C357T基因型CT/TT是除高血压病史、发病年龄外,IgA肾病患者发生大量蛋白尿的独立保护因素(P =0.012,OR =0.485,95％ CI0.275 ～0.854)。结论 本研究检测到8种基因多态性,其中NPHS2基因C357T 的T等位基因是中国北方IgA肾病患者发生蛋白尿以及大量蛋白尿的保护因素。     

Clinical significance of determination of urinary albumin, beta 2 microglobulin and Tamm-Horsfall protein in diabetics

Twenty-four hour urinary albumin (Alb) beta 2 microglobulin (beta 2m) and Tamm-Horsfall protein (THP) were measured by radioimmunoassay in 69 diabetics and 23 normal controls. The excretion of urinary Alb, beta 2m and THP in the patients with diabetic nephropathy was found to be different from that of normal controls. The abnormality of excretion of Alb, beta 2m and THP is particularly evident in the patients with clinical diabetic nephropathy. These results indicate that the renal lesions of diabetes mellitus exist not only in the glomeruli but also in the proximal and/or distal tubules. There was a significantly positive correlation between THP excretion and creatinine clearance (less than 127 ml/min/1.73m2). The findings suggest that the excretion of urinary THP is a valuable index for evaluating the damages of nephrons. It is believed that determination of urinary Alb, beta 2m and THP in diabetics is beneficial to early detection of the sites and degree of the renal lesions.     

Relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy

We demonstrated previously that the blood pressure of patients with IgA nephropathy becomes salt sensitive as renal damage progresses. We also showed that increased urinary angiotensinogen levels in such patients closely correlate with augmented renal tissue angiotensinogen gene expression and angiotensin II levels. Here, we investigated the relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. Forty-one patients with IgA nephropathy consumed an ordinary salt diet (12 g/d of NaCl) for 1 week and a low-salt diet (5 g/d of NaCl) for 1 week in random order. The salt-sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linking 2 data points obtained during consumption of each diet. The urinary angiotensinogen:creatinine ratio was significantly higher in patients who consumed the ordinary salt diet compared with the low-salt diet (17.5 μg/g [range: 7.3 to 35.6 μg/g] versus 7.9 μg/g [range: 3.1 to 14.2 μg/g] of creatinine, respectively; P<0.001). The sodium sensitivity index in our patients positively correlated with the glomerulosclerosis score (r=0.43; P=0.008) and changes in logarithmic urinary angiotensinogen:creatinine ratio (r=0.37; P=0.017) but not with changes in urinary protein excretion (r=0.18; P=0.49). In contrast, changes in sodium intake did not alter the urinary angiotensinogen:creatinine ratio in patients with Ménière disease and normal renal function (n=9). These data suggest that the inappropriate augmentation of intrarenal angiotensinogen induced by salt and associated renal damage contribute to the development of salt-sensitive hypertension in patients with IgA nephropathy.     

Immunological comparison of patients with rheumatoid arthritis with and without nephropathy.

Serum immunoglobulins IgG, IgA, and IgM, serum complement components C3 and C4, circulating immune complexes, antinuclear antibodies, and rheumatoid factor were measured in 56 patients with rheumatoid arthritis (RA) and nephropathy (23 with mesangial glomerulopathy; 13 with membranous glomerulonephritis; and 20 with amyloidosis) and 35 patients with RA without nephropathy (controls). Renal immunofluorescence findings in patients with mesangial glomerulopathy were compared with the serologic data. There were no differences in the occurrence of rheumatoid factor, antinuclear antibodies, and circulating immune complexes and the concentrations of serum complement C3 and C4 between various RA nephropathy groups and controls. Serum IgA and IgM concentrations were significantly higher in patients with mesangial glomerulopathy and amyloidosis than in controls. In patients with mesangial glomerulopathy glomerular IgM, IgA, and C3 were the most prominent findings in immunofluorescence examination. The serum IgA concentration was significantly higher in those patients with mesangial glomerulopathy with mesangial IgA deposits than in those without (4.97 (SD 1.03) g/l v 2.07 (1.21) g/l). The highest serum IgA concentrations (5.08 (1.39) g/l) were seen in the four patients with IgA glomerulonephritis. The prevalence of IgA glomerulonephritis in the renal biopsy material of the patients with RA was 5%, which possibly differs little from that seen in the general population. The results suggest that circulating immune complexes may not have any major role in the pathogenesis of various nephropathy types in patients with RA, contrary to their role in most extra-articular manifestations of RA.     

Renal handling of glycated albumin in non-insulin-dependent diabetes mellitus with nephropathy

Renal handling of glycated albumin in diabetic nephropathy was examined by studies on renal selectivity for glycated albumin in 23 normal controls and 52 patients with non-insulin-dependent diabetes mellitus (NIDDM) with various degrees of nephropathy. The serum and urinary levels of glycated albumin were measured by enzyme-immunoassay with monoclonal antibody to glucitol-lysine residues in human glycated albumin. The diabetic patients were divided into 3 groups according to the albumin index (AI): patients with normoalbuminuria [AI less than or equal to 30 mg/g creatinine(Cr)], with microalbuminuria (30 less than AI less than or equal to 270 mg/g Cr), and with macroalbuminuria (AI greater than 270 mg/g Cr). The renal selectivity for glycated albumin was calculated from the ratio of the urinary to serum level of glycated albumin. In the controls, the renal selectivity was as high as 4.40 +/- 0.48, and significantly higher than those in patients with normo- (2.87 +/- 0.29), micro- (1.72 +/- 0.20) and macroalbuminuria (1.26 +/- 0.23). The renal selectivity was inversely correlated with the AI in diabetic patients (r = -0.58, P less than 0.01). These data indicate that glycated albumin was selectively excreted in the urine and that the renal selectivity in diabetic patients gradually decreased to a value of 1 with increase in albuminuria. When the patients with normoalbuminuria were divided into two subgroups with high and low albumin excretion, the renal selectivities for glycated albumin in both subgroups were still significantly lower than that in controls. These results suggested that early diabetic nephropathy which cannot be detected clinically by albuminuria can be diagnosed by measurement of renal selectivity for glycated albumin.     

CD44在IgA肾病中的表达及临床意义

目的研究CD44在IgA肾病各病变阶段肾组织中的表达及其与临床指标之间的关系,探讨CD44在IgA肾病发病机理中的生物学意义.方法应用免疫组织化学S-P法检测34例IgA肾病肾组织、6例正常肾组织中的CD44的表达情况,同时测定IgA肾病患者的24小时尿蛋白定量、血压、血肌酐(Cr)、肌酐清除率(Ccr)等.分析不同临床分组、病理分级、有无高血压、蛋白尿程度、血Cr水平等对CD44表达的影响.结果 CD44主要于系膜增生、新月体、小管间质炎性细胞浸润的部位表达,于细胞性新月体表达最强.整个球性硬化时,CD44表达近消失.CD44表达与蛋白尿程度正相关(P＜0.05);与血cr水平无明显相关性(P＞0.05);有高血压者CD44表达阳性率92%(23/25),无高血压者为33.3%(3/9),两者比较有显著性差异(P＜0.01).CD44在肾组织中的表达与IgA肾病患者的年龄、性别无相关性.结论 CD44与IgA肾病的活动性进展有关,CD44可作为判定IgA肾病早期进展的可靠指标.     

Prognostic values of serum concentration and urinary excretion of interleukin-1 receptor antagonist and tumor necrosis factor receptors type I and II in patients with IGA nephropathy

Interleukin-1 receptor antagonist (IL-1ra) and tumor necrosis factor soluble receptors (sTNFR) type I and II reducing the activity of IL-1 and TNFalpha may inhibit inflammatory reactions. The aim of the study was to assess whether serum and urine IL-1ra and sTNFR measurements may be useful as the early predicting factors in patients with IgA nephropathy. Twenty seven patients (16 males, 11 females), mean age 41.6 +/- 22.3 years with biopsy-proven IgA nephropathy and nephrotic-range proteinuria were included in this study. Serum concentrations (sIL-1ra, ssTNFR I and II) and urinary excretions (uIL-1ra, usTNFR I and II) of IL-1ra, sTNFR I and II had been measured before the treatment was instituted. After 12 months of therapy with steroids and cyclophosphamide, the patients were divided into two subgroups i.e. R - responders, and NR - nonresponders according to the treatment results. The control groups comprised 8 healthy people. IL-1ra serum concentration and urinary excretion were lower in the patients than in the controls (202 vs 330 ng/ml and 970 vs 1607 ng/mg creatinine respectively; p < 0.05 both). Serum concentrations and urinary excretion rates of sTNFR 1 (5.1 vs 1.7 ng/ml and 4.1 vs 1.1 ng/mg creatinine respectively) and sTNFR II (14.4 vs. 5.0 ng/ml and 8.3 vs. 4.4 ng/mg creatinine respectively) were higher (p < 0.05 each) in the patients than in the controls. The subdivision of patients and their classification according to achieved treatment results showed no statistically significant differences between initial interstitium volume neither concentration of serum total protein, serum creatinine or proteinuria and glomerular filtration rate in R and NR subgroups. Initial IL-1ra serum concentration, its urinary excretion and sTNFR type I and II urinary excretion rates were significantly higher in R than NR (sIL-1ra - 297 vs 167 ng/ml, p < 0.05; uIL-1ra 1360 vs 87 ng/mg Cr, p < 0.01; and ssTNFR I 5.2 vs 2.2 ng/mg Cr, p < 0.05; ssTNF RII14 vs 6 ng/mg Cr, p < 0.05). However, serum concentration and urinary excretion of sTNF R type I and II were significantly higher in R and NR subgroups than in controls (p < 0.05 both), sIL-1ra and uIL-1ra were significantly lower in R and NR than in healthy subjects. The results of evaluations of serum concentration and urinary excretion of IL-1ra showed similar values to control group results only in responders. No statistically significant differences between sIL-1ra or/and uIL-1ra in both R and control groups were found. Increased serum concentration and urinary excretion of IL-1ra correlates with better prognosis for remission of proteinuria and lower risk of deterioration of kidney function. Those assessments may be helpful as a part of initial screening in patients with IgA nephritis and heavy proteinuria. In contrast the evaluation of both serum and urinary TNF RI and II seems to have no predictive value.     

The course of incipient diabetic nephropathy: studies of albumin excretion and blood pressure

With the aim of defining the transitional phase from normal or near normal albumin excretion to overt diabetic nephropathy, 23 male diabetics of more than 7 years' duration, below 40 years of age and a baseline urinary albumin excretion above 15 micrograms/min but without clinical proteinuria (incipient diabetic nephropathy) were studied. For comparison 18 normals, 23 diabetics with normal albumin excretion and 10 patients with overt nephropathy were also examined. Diastolic blood pressure (DBP) was elevated to 88 +/- 9 mmHg (mean +/- S.D.) compared to patients with normal urinary albumin excretion: 80 +/- 7 (S.D.) (2p = 0.13%) but was below pressures in patients with overt diabetic nephropathy 109 +/- 15 (2p = 0.002%). Glomerular filtration rate (GFR) was elevated to 142 +/- 21 ml/min (mean +/- S.D.) compared to 132 +/- 9 in patients with normal urinary albumin excretion (2p = 4.3%). Renal plasma flow (RPF) was not altered. Renal vascular resistance (RVR) was increased (0.200 +/- 0.035) compared to that of patients with normal urinary albumin excretion (0.180 +/- 0.025) (2p = 3.8%). In a longitudinal study of 10 of the patients with incipient nephropathy, followed for 4.9 (Mean) years, urinary albumin excretion increased significantly during the observation period, the yearly increase rate being 19 +/- 22% (mean +/- S.D.). DBP increased from 84 +/- 9 to 93 +/- 13 (2p = 3.8%) in 6 patients followed for more than 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular charge selectivity in non-insulin-dependent diabetes mellitus

To elucidate the stage of the charge selectivity defect in diabetic nephropathy, urinary excretions of IgG1 and IgG4 were measured in patients with non-insulin-dependent diabetes mellitus (NIDDM) and healthy controls. The molecular weights of IgG1 and IgG4 were the same but their isoelectric points were different. Therefore, by measuring both urinary IgG1 and IgG4 excretions, the stage of charge selectivity impairment in the nephropathy of NIDDM may be elucidated. Results were expressed as urinary excretion rate (IgG1 ER, IgG4 ER) and compared between diabetic patients with different urinary excretion rates of albumin (AER). IgG4 ER increased to the stage in which AER was more than 10 μg/min, whereas IgG1 ER did not increase to the stage of AER between 10 and 100 μg/min. This finding suggests that the charge selectivity defect in the kidney of the NIDDM patient is present at the stage when AER is more than 10 μg/min.     

Th1/Th2平衡关系与IgA肾病临床、病理表现的相关性分析

目的探讨辅助性T（Th）1/Th2细胞平衡与IgA肾病（IgAN）临床、肾脏病理表现的相关性。方法采用流式细胞术检测40例IgAN患者与20例健康人对照组外周血Th1、Th2值;收集IgAN患者慢性扁桃体炎史和反复发作性肉眼血尿史,血清胆固醇（Tch）、三酰甘油（TG）、IgG、IgA、内生肌酐清除率（Ccr）,24 h尿蛋白及肾脏病理表现;并了解IgAN患者以上情况与Th1/Th2比例的相关性。结果 IgAN患者外周血中Th2细胞比例为（1.77±0.90）%,较健康对照组的（1.18±0.15）%升高（P〈0.01）。慢性扁桃体炎对Th1/Th2比例无明显影响;有反复发作性肉眼血尿的IgAN患者Th1细胞比例（8.50±4.68）%及Th1/Th2值（4.10±2.01）均较无反复发作性肉眼血尿IgAN患者高（P〈0.05）,24 h尿蛋白定量大于1.0 g/d IgAN患者的Th1细胞比例（2.55±1.20）%及Th1/Th2值（1.58±0.43）均较小于1.0 g/d的患者（P〈0.01）;多元线性回归分析显示IgAN患者外周血Th1/Th2比值与血清中IgG/IgA值存在着正相关关系。结论 IgAN患者存在Th2细胞型免疫表达增强,可能与IgA肾病的免疫机制有关;反复发作性肉眼血尿及24 h尿蛋白小于1.0 g/d的IgAN患者外周血的Th细胞亚群呈Th1偏移;IgAN患者的血清中IgG/IgA值对外周血中Th1/Th2比值存在着正相关影响。     

Beneficial effects of olmesartan and temocapril on urinary liver-type fatty acid-binding protein levels in normotensive patients with immunoglobin A nephropathy

BACKGROUND: Liver-type fatty acid-binding protein (L-FABP) is a clinical biomarker of tubulointerstitial damage, which plays an essential role in the progression of chronic kidney disease (CKD), including immunoglobin A (IgA) nephropathy. The effect of combination therapy with the angiotensin receptor blocker (ARB) and the angiotensin-converting enzyme inhibitor (ACEI) on CKD has not been elucidated. METHODS: Twenty-four normotensive patients with IgA nephropathy were randomly assigned to receive olmesartan 10 mg/day, temocapril 2 mg/day, or combination therapy with both drugs. Urinary levels of L-FABP as well as 8-hydroxydeoxyguanosine (8-OHdG) and protein excretion were measured before and after 3 months of treatment. The chronicity index and activity index were also assessed by histopathologic findings. RESULTS: Urinary levels of L-FABP and 8-OHdG were higher in patients with IgA nephropathy than in age-matched and sex-matched healthy controls (122.5 +/- 25.5 v 6.4 +/- 3.8 mug/g.creatinine, P < .001; and 22.6 +/- 4.4 v 4.8 +/- 1.4 ng/mg.creatinine, P < .01, respectively). Urinary levels of L-FABP were correlated with those of 8-OHdG (baseline, P = .0001; after 3 months, P = .008) and the severity of proteinuria (baseline, P = .0015; after 3 months, P = .0001). The percent reductions in urinary levels of L-FABP and 8-OHdG, protein excretion, and activity index after 3 months were greater in the combination therapy group, compared with each monotherapy group of olmesartan (P < .05) and temocapril (P < .05). CONCLUSIONS: The data suggest that a combination therapy of ARB plus ACEI has a greater beneficial effect on renal injury compared with monotherapy using ARB or ACEI in normotensive patients with IgA nephropathy.     

Urinary N-acetyl-beta-D-glucosaminidase excretion in insulin-dependent diabetes mellitus: relation to microalbuminuria, retinopathy and glycaemic control

N-Acetyl-beta-D-glucosaminidase (NAG) excretion was measured in early morning urine samples from 133 Albustix-negative, normotensive insulin-dependent diabetic patients and 89 non-diabetic controls. Urinary NAG activity was determined using a chromogenic substrate, 2 methoxy-4-(2'-nitrovinyl)-phenyl 2-acetamido-3-deoxy-beta-D-glucopyranoside, and expressed as mumol MNP released/hour/mmol of creatinine. Overall, diabetic patients were found to have a significantly elevated mean urinary NAG activity (p less than 0.01) compared to controls. Within the diabetic patients urinary NAG activity was significantly elevated in patients with either microalbuminuria (p less than 0.001) or "poor" glycaemic control (p less than 0.001), but not in those with retinopathy (p = 0.117). Three-way analysis of variance revealed that the relationship of raised urinary NAG to microalbuminuria and "poor" glycaemic control were statistically independent. Elevated urinary NAG excretion in insulin-dependent diabetes mellitus appears to be associated with early diabetic nephropathy and poor long-term glycaemic control.     

URINARY EXCRETION OF HUMAN EPIDERMAL GROWTH FACTOR IN THE VARIOUS STAGES OF DIABETIC NEPHROPATHY

Epidermal growth factor (EGF) is a polypeptide mitogen first isolated from mouse submaxillary glands and later from human urine. We have examined the pattern of urinary excretion of human EGF (hEGF) in normal subjects and in diabetic patients with varying degrees of nephropathy. hEGF was measured by homologous radioimmunoassay and expressed in terms of urinary creatinine excretion. On the basis of their albumin excretion rate, the diabetic patients were divided into those with normoalbuminuria (albumin excretion rate 3.5 (1.4-9.8) micrograms/min; mean (range)), microalbuminuria (albumin excretion rate 75 (30-128) micrograms/min) and macroalbuminuria (289 (169-879) micrograms/min). The albumin excretion rate for the normal subjects was 3.7 (1.6-9.7) micrograms/min. The mean (range) hEGF excretion (nmol hEGF/mmol creatinine) was 0.69 (0.47-1.29) for 19 healthy subjects, 0.60 (0.16-1.36) for the normoalbuminuric group (n = 18; NS), 0.47 (0.10-0.83) for the microalbuminuric patients (n = 19; P less than 0.001 vs controls and normoalbuminuric diabetics) and 0.38 (0.10-0.63) for the macroalbuminuric group (n = 18; P less than 0.001 vs controls and normoalbuminuric diabetics). There was an inverse correlation between albumin excretion rate and hEGF: creatinine ratio (r = -0.49; P = 0.02). These results show a progressive decline in hEGF excretion in diabetic patients with varying degrees of nephropathy and do not support the hypothesis that increased kidney size seen in early nephropathy is due to excessive amounts of EGF in the urine.     

Elevated urinary prostaglandin excretion and the effect of indomethacin on renal function in incipient diabetic nephropathy

We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and urinary albumin excretion in incipient diabetic nephropathy (defined as urinary albumin excretion between 30 and 300 mg/24 h (microalbuminuria) in two out of three sterile ketone-free 24-h urine collections in patients having insulin-dependent diabetes mellitus (IDDM) without hypertension or other kidney disease). The urinary excretion of prostaglandin E2 was significantly elevated in 8 insulin-dependent diabetic patients with incipient nephropathy as compared with 9 normoalbuminuric IDDM patients and 11 healthy controls: 317 (182-1273); 95 (67-225); 132 (54-263) pg/min, respectively (2p less than 0.01). Glomerular filtration rate (single bolus 51Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within 2 weeks in 8 females having IDDM with incipient nephropathy. The study design was a randomized double-blind trial with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E2 excretion (73%) (2p less than 0.01), urinary albumin excretion rate diminished from 207 (63-253) to 87 (49-147) mg/24 h (2p less than 0.01), fractional clearance of albumin declined (70%) (2p less than 0.01). Glomerular filtration rate remained stable (108 (88-133) versus 110 (95-142) ml/min). Blood glucose and blood pressure were comparable during the placebo and indomethacin treatment (12.6 +/- 3 versus 13.4 +/- 5 mmol/l and 122/79 +/- 3/9 versus 122/82 +/- 4/10 mmHg, respectively). Our results suggest that enhanced glomerular synthesis of vasodilating prostaglandins may accelerate microalbuminuria in incipient diabetic nephropathy.     

Kidney function and retinol status in type 2 diabetes mellitus patients

Kidneys play an important role in retinol turnover. We postulated that retinol homeostasis is disturbed in diabetic nephropathy. The aim of this research was to study the effect of kidney impairment on urinary excretion and on serum concentrations of retinol in type 2 diabetes mellitus patients. For this purpose, 41 type 2 diabetes patients and 9 sex -and age-matched healthy subjects were enrolled. Serum and urinary retinol and retinol-binding protein (RBP) were assessed by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. The study showed that 17 out of 41 diabetic patients (41.5%) and none of the controls excreted retinol in urine (P < 0.02). Retinol excretion in the urine in these patients was 1.5-fold more prevalent than hypercreatininemia. Urinary retinol significantly correlated with clinically diagnosed nephropathy (P = 0.02). All but one of the patients with hypercreatininemia excreted retinol in the urine. Serum retinol and RBP in patients with hypercreatininemia were higher than in controls (P < 0.002). Values of urinary retinol, unlike urinary RBP, albumin and total protein, did not overlap between patients and controls. Our results indicate that (i) urinary retinol is a specific sign of tubular damage in type 2 diabetic patients and (ii) urinary retinol enables a more clear-cut identification of proximal tubule dysfunction in type 2 diabetes patients than urinary RBP or albumin.     

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.     

Protein-loading test, urinary albumin excretion and renal morphology in diagnosis of subclinical diabetic nephropathy.

The acute effects of protein loading (1.5 g kg-1) on glomerular filtration rate (GFR) and urinary albumin excretion (UAE) were investigated in 23 type-I diabetic patients with no clinical nephropathy, and in 7 healthy subjects (controls). The results were compared with renal morphology data. In controls and in 14 diabetic patients (group 1) GFR increased by 27 and 37%, respectively, corresponding to normal renal reserve, but in 9 patients (group 2) GFR decreased by 20%, indicating the absence of a renal reserve. Microalbuminuria was found in none of the patients in group 1 and in 50% of patients in group 2. Two hours after the load UAE increased in all groups, but the increase was most marked in group 2, despite the fall in GFR. The two groups of patients did not differ with regard to the duration and control of diabetes, but differed markedly in terms of baseline GFR (131 vs. 195 ml min-1, P less than 0.01, in groups 1 and 2, respectively). Renal morphology showed minimal non-specific glomerular injury in group 1, and signs of glomerulosclerosis in group 2. We conclude that the impaired renal response to protein load precedes other subclinical manifestations of diabetic renal injury, and may be useful in the diagnosis of latent diabetic nephropathy.     

Clinical usefulness of measuring urinary polyol excretion by gas-chromatography/mass-spectrometry in type 2 diabetes to assess polyol pathway activity

INTRODUCTION: Decreased myo-inositol levels and increased activity of the polyol pathway have been proposed to play a role in causing diabetic microvascular complications. There are few clinical methods for examining the activity of the polyol pathway in diabetic patients. We assessed the effect of changes in glycemic control on polyol pathway activity by measuring urinary polyol excretion. MATERIALS AND METHODS: Gas-chromatography/mass-spectrometry (GC/MS) was used to assess the urinary excretion of glucose and polyols (myo-inositol, sorbitol, and fructose) in 50 patients who had type 2 diabetes without nephropathy and 20 healthy subjects. RESULTS: In the diabetic patients with poor glycemic control, urinary sorbitol levels were significantly increased and urinary myo-inositol excretion was approximately 6.5-fold higher than in healthy controls (33.0+/-6.5 vs 221.7+/-45.9 mg/day, mean+/-SE, P<0.01). During strict glycemic control, some patients (Group A) showed simultaneous disappearance of glucosuria and normalization of the urinary excretion of myo-inositol (<50 mg/day) and, while others (Group B) showed delayed normalization of urinary myo-inositol excretion. Group B showed significantly higher urinary myo-inositol, sorbitol, and fructose excretion than Group A at the time of disappearance of glucosuria. These findings suggest that patients in Group B may have increased polyol pathway activity. CONCLUSION: Even though short-term strict glycemic regulations were established in long-standing hyperglycemic diabetic patients, to normalize the once-exaggerated polyol pathway activities, it was essential to maintain glucosuria-free conditions for some period. Quantitation of urinary polyols using GC/MS appears to be a clinically useful method for assessing polyol pathway activity.     

Decreased Urinary Dopamine Excretion and Disturbed Dopamine/Sodium Relationship in Type 1 Diabetes Mellitus

In Type 1 diabetes an increased total body sodium and an impaired ability to excrete a sodium load have been described. A possible involvement of the renal dopaminergic system in this abnormal sodium handling was evaluated through measurements of the urinary output of dopamine, sodium, the dopamine/sodium correlation, and through examining the effect of a dopamine infusion on urinary sodium excretion. Twenty-four hour urinary dopamine excretion was significantly lower in Type 1 diabetic patients as compared to normal controls. A significant correlation between urinary dopamine and sodium excretion was present in normoalbuminuric Type 1 diabetic patients and in normal controls. However, no such correlation could be found in microalbuminuric patients. The increase in fractional excretion of sodium during a 1 h low-dose dopamine (3 μg kg^?1min^?1) infusion in Type 1 diabetic patients was negatively correlated with diabetes duration. Patients with short duration of diabetes (less than 15 years) had a comparable dopamine-induced increase in fractional excretion of sodium as normal controls. However, patients with longer duration of diabetes (more than 15 years) and microalbuminuric patients displayed no significant changes in sodium output during dopamine infusion. These findings suggest that in Type 1 diabetes mellitus a deficiency of renal dopamine production could be responsible for the impaired sodium handling. Longer duration of the disease and microalbuminuria seem to be associated with an uncoupling of the urinary dopamine/sodium relationship.     

Urinary excretion of retinol-binding protein in type 1 (insulin-dependent) diabetic patients with microalbuminuria and clinical diabetic nephropathy

The urinary excretion of retinol-binding protein (RBP) was studied in 101 insulin-dependent diabetic patients allocated to three groups according to 24-h urinary albumin excretion rate (UAE) (median of three urine collections): group 1 (n=45), normal UAE<30 mg/24h; group 2 (n=27), microalbuminuria (UAE 30–300 mg/24 h); and group 3 (n=29), clinical diabetic nephropathy (UAE>300 mg/24 h). We used 23 healthy subjects as controls. Fractional clearance of RBP (FC-RBP) and its 24-h urinary excretion rate (URBP) were higher in each diabetic group than in healthy subjects, the highest values being found in group 3. Groups 1 and 2 did not differ in URBP and FC-RBP. There was a correlation between FC-RBP and haemoglobin A1c in both the total diabetic cohort (P<0.001) and in diabetic patients in groups 1 and 2 with a glomerular filtration rate of more than 90 ml/min (P<0.05). No correlation was found between FC-RBP and UAE and/or duration of diabetes in any of the diabetic groups. We conclude that the increased urinary excretion of RBP, indicating proximal tubular dysfunction, is already present in normoalbuminuric insulindependent diabetic patients and correlates with metabolic control. Further deterioration in proximal tubular function was not observed in microalbuminuric patients, but is a late event in clinical diabetic nephropathy.