Influence of haemodialysis and renal transplantation on trace element concentrations in children with chronic renal failure

Whole blood levels of Cd and Pb (g/g Hb), serum concentrations of Sr and Zn and their urinary excretion were measured in healthy, renal transplant and dialyzed children by atomic absorption spectroscopy. Furthermore, before and after dialysis the concentrations of these elements were determined in blood/serum as well as in the dialysis fluid. The predialytic concentrations of Cd, Pb and Sr in blood/serum were significantly increased compared to controls. Haemodialysis had only minor effects on whole blood Cd and Pb levels but serum Sr and Zn concentrations increased as a result of high metal levels in dialysis fluid.Children after renal transplantation showed no alterations in Pb, Sr and Zn concentrations compared to healthy children but whole blood Cd was increased.According to the renal function the Pb, Cd and Zn urinary excretion decreased in the following order: healthy, renal transplant and dialysis children. Sr urinary excretion was increased in haemodialysis and renal transplant patients.In conclusion, we found no Zn deficiency. Elevated blood levels of Cd and Pb and elevated Sr serum concentrations in paediatric patients undergoing dialysis and increased Cd whole blood levels in renal transplant children could be of clinical interest. Offprint requests to: Institute of Toxicology of the University of Düsscldorf, Moorenstrasse 5, D-4000 Düsseldorf 1, Federal Republic of Germany     

Lack of association of IL8 gene polymorphisms with familial vesico-ureteral reflux

Vesico-ureteral reflux (VUR) is the most common inherited disorder of the lower urinary tract. Children with VUR are at risk for ongoing renal damage with subsequent infections. IL8 is an important inflammatory mediator which can be produced by epithelial cells of the renal tract in response to a variety of inflammatory stimuli. High serum concentrations of IL-8 have been reported in patients with chronic renal failure. Elevated IL-8 levels have been reported in the urine of patients with VUR and renal parenchymal scarring (RPS). More recently it was reported that urine IL-8 levels remain elevated in infants with VUR even in the absence of a urinary tract infection (UTI). Increased IL-8 expression has been shown to be associated with polymorphism at position -251 (rs4073) of the IL-8 promoter. The aim of this study was to examine the association of IL-8 gene polymorphism with familial VUR in a cohort of 219 siblings from 109 families affected with VUR, the largest such cohort tested to date. RPS was assessed using dimercaptosuccinic acid scintigraphy. Genotyping was performed in 219 siblings with VUR (157 without RPS, 62 with RPS) and 292 controls for the position -251 of IL-8 gene by polymerase chain reaction with tetra primers and gel analysis. Genotype was compared using the chi square test. Statistical significance was taken as a value of P < 0.05. There were no significant differences in IL-8 -251 genotype frequency between VUR patients and controls. Similarly, gender, severity of VUR and renal parenchymal scarring had no effect on IL-8 -251 genotype frequency. Although IL-8 urinary levels have been reported to be elevated in VUR, our data indicate that IL-8 gene is not involved in the pathogenesis of familial VUR or reflux nephropathy.     

Serum levels of vascular endothelial growth factor in children and adolescents with systemic lupus erythematosus

The angiogenic cytokine vascular endothelial growth factor (VEGF) may have a role in the pathogenesis of collagen diseases. We aimed to assess its serum levels in children and adolescents with systemic lupus erythematosus (SLE) and to elucidate its correlation with clinical features, laboratory parameters, and the overall disease activity. This study comprised 25 children and adolescents with SLE and 30 healthy controls. Disease activity was evaluated by SLE disease activity index (SLEDAI) score. Laboratory investigations included complete blood count, erythrocyte sedimentation rate (ESR), urine analysis, 24-h total urinary protein, assay of serum creatinine, ANA, anti-DNA, complement component C3, lupus anticoagulant, and VEGF. Serum levels of VEGF were significantly increased in SLE patients (579.5 +/- 184.7 pg/ml) when compared with controls (113.2 +/- 30.8 pg/ml) (p < 0.0001). VEGF serum levels were significantly increased in patients having renal involvement and neurologic symptoms than those who did not have them (p < 0.0001, p < 0.005, respectively). Serum levels of VEGF were higher in patients with antiphospholipid syndrome, vasculitis, and skin symptoms than those without, but the difference did not reach statistical significance. Meanwhile, they were similar in patients with and without arthritis (p > 0.05). VEGF serum levels were not correlated to age; inversely correlated to platelet count, serum C3 level; and positively correlated to ESR. SLEDAI score was positively correlated to VEGF serum level (r = 0.86, p < 0.0001). VEGF may be relevant to SLE pathogenesis. Its concentration seems to be a marker of SLE activity, which could help in disease monitoring and planning of treatment.     

Familial IPEX syndrome: Different glomerulopathy in two siblings

Immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome (OMIM 304790) is a rare hereditary disorder of the immune regulatory system caused by FOXP3 mutations. The clinical features of this syndrome include a wide spectrum of severe autoimmune diseases and renal involvement, mostly due to tubulointerstitial diseases, in some patients. Glomerulopathy of membranous nephropathy (MN) and minimal change nephrotic syndrome (MCNS), however, have also been reported. We encountered two children with IPEX syndrome from the same family. Interestingly, they had different glomerular lesions: one had MN and the other had MCNS. Herein we describe the cases of these siblings and review the possible mechanisms for the development of two different renal lesions.     

新生儿急性肾功能衰竭血和尿表皮生长因子的动态变化和意义

目的　探讨新生儿急性肾功能衰竭 (ARF)过程中血、尿表皮生长因子 (EGF)的变化及其意义。方法　采用放射免疫分析法 ,测定 17例对照组新生儿和 31例ARF新生儿少尿期、多尿期和恢复期血清和尿EGF水平。结果　肾衰组在少尿期和多尿期血清和尿EGF均显著下降 ,恢复期血清和尿EGF水平恢复至正常。肾衰组少尿期和恢复期尿EGF与同期尿素氮 (BUN)、血肌酐 (SCr)水平呈显著负相关。结论　在新生儿ARF过程中血、尿EGF呈先下降后上升变化趋势 ,反映了肾脏的损害及修复过程     

肾病综合征患儿血清抗增殖蛋白水平

目的研究肾病综合征患儿血清抗增殖蛋白(prohibitin,PHB)蛋白水平及其在肾小管间质早期损伤中的意义。方法应用Western blot对36例原发性肾病综合征患儿血清进行PHB蛋白水平检测,同期正常体检儿童30例为对照组。同时检测两组血清肌酐(Scr)、血尿素氮(BUN)、尿微量蛋白系列[白蛋白/肌酐(ALBU/Cr)、N-乙酰β-D-葡萄糖苷酶/肌酐(NAGU/Cr)、免疫球蛋白G/肌酐(IgGU/Cr)、α1微球蛋白/肌酐(α1-MU/Cr)等]。肾小球及肾小管间质损伤评分参照Katafuchi半定量法进行。结果正常对照组儿童血中未检测到PHB蛋白,肾病综合征患儿血PHB蛋白水平不同程度增高(0.203±0.032比0±0,P<0.05)。伴增生性病变肾病综合征患儿血PHB水平明显高于非增生性患儿。血PHB水平与肾小管间质损伤程度以及肾小球损伤程度均呈明显正相关(r=0.868、0.753,P均<0.001);患儿血PHB水平与尿微量蛋白NAG、IgG呈正相关(r=0.586、0.341,P均<0.001)。结论肾脏疾病患儿血PHB表达明显增高,而且血PHB水平与肾小球及肾小管间质损伤程度明显相关...     

小儿血清、尿半胱氨酸蛋白酶抑制剂C测定及临床意义

目的探讨血清、尿半胱氨酸蛋白酶抑制剂C(CysC)水平的临床应用价值。方法选择136例正常儿童按年龄分组测定血清CysC,其中95例还测定了尿CysC,建立正常儿童不同年龄组血清、尿CysC参考值。测定580例住院肾脏疾病患儿血清、尿CysC浓度,了解各类肾脏疾病两值水平的变化。结果在肾功能损害患者中血清CysC有明显升高,在肾小管受损的患儿中尿CysC明显升高。结论血清CysC对评价肾小球滤过功能有临床价值,是诊断早期肾功能损害的敏感指标。尿CysC在诊断肾小管损害方面有一定应用价值。     

Post‐streptococcal acute glomerulonephritis associated with pneumococcal infection

Streptococcus pyogenes is the most common cause of post‐infectious glomerulonephritis. Described herein is the case of a 5‐year‐old girl with febrile post‐streptococcal acute glomerulonephritis (PSAGN) associated with pneumococcal bacteremia. The chief complaints were fever and macrohematuria without respiratory symptoms. Urinalysis indicated a protein level of 3+. Serological data showed elevated anti‐streptolysin O (ASO) and hypocomplementemia. Blood culture was positive for S. pneumoniae. Her acute renal failure was mild and improved over several days. Although PSAGN was confirmed by elevated ASO and transient hypocomplementemia, the clinical course was consistent with those of several reported cases of AGN associated with pneumococcal infection. To our knowledge, there have been few reports on the relationship between pneumococcal infection and the incidence of PSAGN. We suggest the hypothesis that pneumococcal infection itself could exaggerate the complement reaction leading to PSAGN. It is important to consider PSAGN associated with a microbial infection such as S. pneumoniae when faced with a febrile patient with AGN.     

Nitric oxide synthase gene polymorphisms in children with minimal change nephrotic syndrome

Aims:  Nitric oxide (NO) attenuates many functions within the kidney, and all NO synthase (NOS) isoforms are constitutively expressed in the kidney. But the exact role of NO in renal diseases is still debatable. The aim of the present study was to investigate endothelial ( eNOS ), and neuronal ( nNOS ) NOS gene polymorphisms in children with minimal change nephrotic syndrome (MCNS).
Materials and methods:  Eighty-six Turkish children with clinical MCNS, ranging in age from 2 to 10 years, were compared with 114 healthy age- and sex-matched controls. The glu 298 Asp (G/T) polymorphism of the eNOS, and C276T (C/T) polymorphism of nNOS genes were genotyped using polymerase chain reaction.
Results:  The distribution of GG, TG, and TT genotypes for eNOS was 52%, 33% and 15% in MCNS compared with 61%, 26% and 13% in the controls ( P  > 0.05). The distribution of CC, TC, and TT genotypes for nNOS was 16%, 66% and 18% in MCNS compared with 10%, 43% and 47% in the controls. TT genotype distribution of nNOS was found to be lower in patients ( P  = 0.003). The eNOS and nNOS gene polymorphisms were not associated with gender, positive family history, frequency of relapses, or response to steroid.
Conclusions:  The present study is the first to investigate eNOS and nNOS gene polymorphisms in children with MCNS. The nNOS gene polymorphism may be associated with MCNS in children, but further studies in a larger population with different glomerular diseases are needed to confirm the results.     

Bronchial hyper-responsiveness in atopic dermatitis

Most patients with atopic dermatitis (AD) have symptoms of asthma at some point in their lives, but some do not have any clinical evidence of asthma. Thirty-two patients with AD who had never suffered from bronchial asthma were investigated by the methacholine inhalation test for the presence of bronchial hyper-responsiveness (BHR). Serum immunoglobulin E (IgE) levels, mite specific IgE antibody, peripheral eosinophil counts, serum levels of eosinophil cationic proteins (ECP), and serum levels of major basic proteins (MBP) were determined and a skin test to acetylcholine and adrenaline was performed. The percentage of cases who showed BHR (minimum dose; Dmin < 50 units) was 31.3% in AD patients and 19.0% in 21 healthy controls. In those cases, Dmin of methacholine in AD was significantly lower than that in the controls (P <0.01). Serum MBP levels were significantly higher in AD with BHR than in those without it (P < 0.05). These results indicate that some AD patients without asthma have BHR, and it may be related to serum MBP levels.     

Free carnitine levels in children with steroid–sensitive nephrotic syndrome

BACKGROUND: Carnitine transports long-chain fatty acids across the inner mitochondrial membrane. Carnitine metabolism is disturbed in some renal diseases, such as chronic renal failure. Previous studies have shown that children had normal serum free carnitine (FC) and total carnitine levels in idiopathic nephrotic syndrome, IgA nephropathy, non-IgA nephropathy and focal segmental glomerulosclerosis. The aim of the present study was to determine FC concentrations in plasma and urine during acute and remission periods of steroid-sensitive nephrotic syndrome (SSNS) and its association with hyperlipidemia. METHODS: Plasma and urinary FC concentrations were assayed in 15 children with SSNS in acute and in 16 children in remission period. Six of them were followed-up longitudinally in both periods. RESULTS: Plasma FC concentrations were significantly higher in the acute period of the disease than in the remission period and of the controls. The patients had lower FC levels in the remission period as compared to the controls. Urinary FC concentration was decreased in acute disease period when compared to the remission period and the controls. The FC concentrations in plasma and urine did not correlate with each other. Plasma FC exhibited significant positive correlation with low-density lipoprotein cholesterol, total cholesterol and trygliceride, but negative correlation with high-density lipoprotein cholesterol. CONCLUSIONS: The present study showed disturbed FC concentration in SSNS. Increased plasma and decreased urinary FC levels in acute disease might be associated with its altered renal handling or some extrarenal factors such as hyperlipidemia.     

胱抑素C、纤维蛋白原及24h尿蛋白定量与紫癜性肾炎患儿肾脏病理分级的相关性研究

目的 探讨胱抑素C(CysC)、纤维蛋白原(Fbg)浓度和24 h 尿蛋白定量与紫癜性肾炎(HSPN)患儿肾脏病理分级的相关性和应用价值。方法 收集2011 年1 月至2015 年1 月48 例经肾活检明确诊断为HSPN 患儿的病历资料,根据肾脏病理结果分为Ⅱ a 级及Ⅱ a 级以下12 例、Ⅱ b 级12 例、Ⅲ a 级17 例及Ⅲ b 级及Ⅲ b 级以上7 例。乳胶增强散射免疫比浊法检测所有患儿血清CysC,浊度法检测Fbg 浓度,终点法检测24 h 尿蛋白定量水平;采用Pearson 和Spearman 相关分析对各检测指标之间及各指标与肾脏病理分级之间进行相关分析。结果 血清CysC、Fbg 浓度和24 h 尿蛋白定量在各肾脏病理分级患儿中比较差异均有统计学意义(P<0.05),且各指标水平均随病理分级严重程度增高而上升(P<0.05)。48 例HSPN 患儿血清CysC 和Fbg与24 h 尿蛋白定量之间均呈正相关(分别r=0.51、0.63,P<0.05);Fbg 与血清CysC 之间呈正相关(r=0.55,P<0.05);CysC、Fbg 及24 h 尿蛋白定量与肾脏病理分级之间均呈正相关(分别r=0.66、0.64、0.68, 均P<0.05)。结论 CysC、Fbg 和24 h 尿蛋白定量均能反映肾脏损伤严重程度,对于HSPN 患儿肾脏损伤的严重程度具有较好的判断作用。     

Serum glycoproteins in infantile cirrhosis of liver

To evaluate the importance of total serum proteins and their fractions, fucose and sialic acid in infantile cirrhosis, twenty histopathologically and clinically confirmed cases of infantile cirrhosis were studied. The total serum proteins in normal and cirrhotic infants did not show significant variations, but the albumin fraction showed a fall. The gamme globulin showed a significant rise in infants suffering from infantile cirrhosis as compared to normal control. A significant rise in serum fucose and no change in sialic level was observed in cirrhotic patients in the present study. No variation in levels of alpha₁, alpha₂ globulins and sialic acid in cirrhotic infants reflects that probably most of the sialic acid remains bound with any one or more of these globulin fractions. Decreased ratio of sialic acid and fucose clearly indicates that the origin of these two types of glycoproteins is different.     

RENAL FUNCTION TESTS IN NONACUTE RECURRENT URINARY TRACT INFECTIONS IN CHILDREN

The clinical value of various renal function tests in recurrent urinary tract infections in children has been examined. The study also includes an evaluation of glomerular capacity versus tubular capacity in recurrent urinary tract infections. There was no good correlation between blood urea nitrogen concentration and serum creatinine concentration within the normal limits for these two parameters. When blood urea nitrogen concentration and/or serum creatinine concentration were elevated, a highly significant correlation between the two parameters was found. When relating blood urea nitrogen concentration to the clearance of inulin an elevation of blood urea nitrogen concentration was not found until the filtration rate was below 50 ml/min/1.73 m² b.s. The tubular functions were examined by studies of (a) the concentrating capacity, (b) the diluting capacity, (c) sodium reabsorption and id) renal acid-base regulation. The concentrating capacity was determined by two screening tests, maximal urine osmolality after 19 hours of fluid and food deprivation with or without injection of pitressin tannate, and by free water reabsorption. The administration of exogenous pitressin had no significant effect on maximal urine osmolality. There was a highly significant correlation between free water reabsorption and maximal urine osmolality. A highly significant correlation was also found between free water reabsorption and glomerular filtration rate. Diluting capacity was evaluated by determining minimum urine osmolality and free water clearance. A highly significant correlation between minimum urine osmolality and free water clearance was obtained. There was a good correlation between free water clearance and glomerular filtration rate. When sodium reabsorption is depressed below normal, urine sodium concentration during hydropenia is abnormally low. A normal standard bicarbonate level does not exclude a defect in renal acidifying mechanisms. A defect renal acidifying capacity could be found even in patients with normal filtration rates indicating that renal acidifying capacity might be the first sign of renal damage in children with recurrent urinary tract infections.     

风湿热患者血清新蝶呤的改变

目的 探讨风湿热患者血清新蝶呤的改变及其临床意义。方法 用ELISA法检测急性风湿热风湿活跃期(活动期)、慢性风湿性心脏病风湿静止期(静止期)及健康对照组血清新蝶呤的浓度。结果 ①活动期血清新蝶呤浓度(7.84±6.31nmol/L)明显高于静止期(4.31±2.59nmol/L)(P<0.05)及健康对照组(2.91±2.26nmol／L)(P<0.01);②静止期与健康对照组比较,血清新蝶呤浓度差异无显著性(P>0.05)。结论 风湿热患者血清新蝶呤在活动期增加,静止期下降,血清新蝶呤水平能反映疾病活动性,是风湿热细胞免疫激活的良好指标。     

Predisposing Factors for Nephrolithiasis and Nephrocalcinosis in Cystic Fibrosis

Objective

Cystic fibrosis (CF) is characterized by chronic pulmonary disease, insufficient pancreatic and digestive function, and abnormal sweat concentration. There is controversy about predisposing factors of nephrolithiasis and nephrocalcinosis in patients with cystic fibrosis. We assessed the results of metabolic evaluation in patients with cystic fibrosis and its correlation with nephrocalcinosis.

Methods

Forty five CF patients, mean age 47.1 months, were enrolled in the study. No one had past history of nephrolithiasis and/or nephrocalcinosis. The records were reviewed for clinical characteristics and all patients underwent metabolic evaluation including serum electrolyte measurements and spot urine analysis. Ultrasonography was performed in all patients to detect nephrocalcinosis and urolithiasis.

Findings

Nephrocalcinosis was found in 5 (11%) patients. No patient had clinical symptoms of nephrolithiasis and/or micro/macroscopic hematuria. Metabolic evaluation of the CF patients versus normal reference values showed decreased serum uric acid in 48.8%, elevated serum phosphate in 24.4%, and urine oxalate excretion in 51%. Metabolic evaluation of the nephrocalcinosis positive patients versus nephrocalcinosis negative group showed no statistical difference in serum electrolytes. The mean value of urine calcium excretion was lower in patients with nephrocalcinosis (P=0.001). Despite lack of any significant correlation, higher numerical hyperoxaluria was observed in patients with severe steatorrhea. There was no statistical correlation between steatorrhea and urine calcium as well as oxalate excretion.

Conclusion

Hypocalciuria in the nephrocalcinotic CF patients may be seen. It can be hypothesized that hypocalciuria may be due to a primary defect in renal calcium metabolism in CF patients.     

Are fibroblast growth factor 23 concentrations in renal transplant patients different from non‐transplanted chronic kidney disease patients?

Filler G, Liu D, Sharma AP, Grimmer J. Are fibroblast growth factor 23 concentrations in renal transplant patients different from non‐transplanted chronic kidney disease patients?
Pediatr Transplantation 2012: 16: 73–77. © 2011 John Wiley & Sons A/S. Abstract: To compare the pattern of serum FGF23 levels in pediatric renal transplant recipients and GFR‐matched controls. We performed a cross‐sectional matched pair study in 19 stable pediatric renal transplant recipients and 19 GFR‐matched controls with native CKD. After assessment for normal distribution, demographic and bone metabolism parameters were compared with Student’s t‐test, Wilcoxon’s matched pairs (for non‐normal distribution) test, and correlation analysis. The groups were comparable for anthropometric parameters, cystatin C eGFR (71.10 ± 37.28 vs. 76.11 ± 26.80 mL/min/1.73 m²), cystatin C, urea, creatinine, intact PTH, pH, CRP, alkaline phosphatase, phosphate, calcium, ionized calcium, FGF‐23 (63.44 [IQR 38.42, 76.29], 49.92 [IQR 42.48, 76.97]), albumin, and urinary calcium/creatinine ratio. The renal transplant patients had significantly lower 25‐(OH) vitamin D levels (66.63 ± 17.54 vs. 91.42 ± 29.16 ng/mL), and higher 1,25‐(OH)₂ vitamin D levels (95.78 ± 34.54 vs. 67.11 ± 35.90 pm ). FGF‐23 levels correlated negatively with cystatin C eGFR (r = ?0.3571, p = 0.02770) and positively with PTH (r = 0.5063, p = 0.0026), but not with serum phosphate (r = 0.2651, p = 0.1077). We conclude that the increase in FGF23 levels with GFR decline in pediatric renal transplant patients remains similar to that in the patients with CKD. The relationship between FGF23 and serum vitamin D needs further evaluation.     

Serum sialic acid, hs-CRP and oxidative stress parameters in obese children

BACKGROUND: Obesity is a common health problem that is rapidly increasing among children. Obesity is accompanied by a high incidence of atherosclerosis, arterial hypertension and type 2 diabetes mellitus. We tested the hypothesis that the risk for atherosclerosis may be increased in obese children and measured some risk factors for atherosclerosis. PATIENTS AND METHODS: We determined sialic acid levels and investigated correlations with malondialdehyde (MDA), susceptibility to oxidation, total thiol concentrations, glucose and lipid profile in 39 obese (BMI 26.6 +/- 3.9) and 33 sex- and age-matched healthy children (BMI 15.9 +/- 1.7). RESULTS: MDA concentrations, susceptibility to oxidation and hs-CRP were significantly higher in obese children than controls. Sialic acid and total thiol concentrations were higher in controls but this did not reach statistical significance. Total cholesterol, LDL-cholesterol and glucose concentrations were significantly higher in the obese group and there was a positive correlation between BMI and MDA, susceptibility to oxidation, hs-CRP and glucose concentrations, and a negative correlation between BMI and HDL-cholesterol. Although sialic acid levels were not different between the groups, they showed a correlation with hs-CRP. CONCLUSIONS: A higher risk was found in obese children in relation to oxidative stress parameters, hs-CRP and lipid profile, and this risk showed a positive correlation with BMI. These results are important because children will encounter this increased risk for a longer time than adults, and taking care of obesity in childhood is especially important.     

Long-term prognosis of poststreptococcal acute glomerulonephritis

Five hundred and eighty-eight patients diagnosed as having PSAGN were treated at our University Hospital and called in for a reevaluation study in 1988 to determine the long-term prognosis of the disease. Fifty-nine patients responded to the follow-up call, all of them being in good physical health. The blood pressure, urinalysis, serum creatinine, blood urea and beta 1C globulin levels were within normal limits. These results led us to the conclusion that the long-term prognosis was favorable in our PSAGN patients since chronic renal failure had not been encountered.     

Serum and urinary cytokine homeostasis and renal tubular function in children with type 1 diabetes mellitus

AIM: To explore the relationships between tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and urinary N-acetyl-beta-D-glucosaminidase (NAG) and the function of renal proximal tubules in children with type 1 diabetes mellitus (DM1). METHODS: Fifty-six children with DM1 and 35 healthy controls were analyzed. We measured NAG (A and B isoforms) in urine as well as serum TNFalpha and urinary IL-6. RESULTS: The children with DM1 with microalbuminuria (group A) had significantly higher urinary IL-6 and serum TNFa than the children without microalbuminuria (group B). The diabetic patients with no sign of nephropathy showed significantly higher TNFalpha and NAG and its A and B isoforms in urine compared to the healthy group. Additionally, groups A and B both showed a positive significant correlation between serum TNFalpha and urinary isoform B. CONCLUSIONS: From our pilot results it appears that TNFalpha might be a sensitive marker of damage to the renal proximal tubules occurring prior to microalbuminuria. Conversely, the increase in NAG and its isoform B activity in patients with no clinical sign of diabetic nephropathy may indicate the onset of microalbuminuria.