Early diagnosis of endemic nephropathy

Urinary alpha(1)-microglobulin as a tubular marker and albumin as a glomerular marker were measured in 373 subjects living in a typical endemic village of Kaniza, Croatia, previously classified as diseased, suspect, 'at risk' and others according to the criteria used for the diagnosis of endemic nephropathy. Based on the excretion pattern of alpha(1)-microglobulin and albumin and its extent, significant tubular with significant glomerular proteinuria was found in seven diseased subjects. Significant tubular proteinuria with slight glomerular proteinuria was found in one diseased subject, while another diseased subject had slight tubular with significant glomerular proteinuria. Significant tubular with significant glomerular proteinuria was found in only one suspect subject. Also, significant tubular proteinuria was established in one other subject.     

Urinary excretion of albumin and beta 2-microglobulin in a population from an area where Balkan nephropathy is endemic.

The urinary excretion of albumin and beta 2-microglobulin in a population of 294 persons, living in an area where Balkan nephropathy is endemic, has been studied. In fifty-six (about 19%) of the subjects the beta 2-microglobulin concentration was above the +2 SD level for a reference group of healthy individuals from non-endemic areas. Albumin elevation was found in forty-four (about 15%) of the cases. In twenty-one of the subjects the urinary concentration of both beta 2-microglobulin and albumin were increased, in sixteen of these cases the relationship between the two proteins was consistent with tubular proteinuria. An increased beta 2-microglobulin excretion is considered to be a sign of Balkan nephropathy. Radioimmunoassay of the protein is sensitive enough to detect tubular proteinuria at an early stage and is suggested as a suitable screening test for the disease.     

Characteristics of proteinuria in endemic nephropathy

Subjects living in the endemic area of Posavina round Slavonski Brod have a significantly greater incidence of proteinuria (13.6%) than those living under the same conditions in the area where endemic nephropathy has not been observed (5.5%). Following determination of the grade and type of proteinuria, physiologic proteinuria was found in 36% of subjects from the endemic area. In nonphysiologic proteinuria the incidence of tubular proteinuria was 41%. A slight selective glomerular proteinuria was found in 51%, and other types of proteinuria in 8% of subjects. Tubular proteinuria was significantly higher in the endemic area than in the control area. The subjects with tubular proteinuria from the endemic area excrete significantly greater amounts of beta 2-microglobulin and light immunoglobulin chains.     

Relationship between the urinary excretion of albumin and retinol-binding protein in insulin-dependent diabetics

The glomerular and proximal tubular function of the diabetic kidney was investigated. The urinary excretion (relative clearance) of albumin, a marker of glomerular function, and retinol binding protein (RBP), a low molecular weight (LMW) protein and marker of proximal tubular function, was determined in insulin-dependent diabetics. No correlation between the relative clearances of albumin and RBP was observed. LMW proteinuria without microalbuminuria was observed in 27 patients which suggests that tubular dysfunction may be an early stage in the development of diabetic nephropathy. Microalbuminuria was found in 16 patients while a mixed type of proteinuria (microalbuminuria and LMW proteinuria) was present in 56 patients several of whom had advanced nephropathy with elevated serum levels of RBP and creatinine. It is suggested that a combination of tubular and glomerular malfunction may be responsible for some cases of mixed proteinuria.     

Tubular secretion of Tamm-Horsfall protein in type 1 (insulin-dependent) diabetes mellitus using a simplified enzyme linked immunoassay.

The relationship between glomerular and tubular dysfunction and metabolic control in type 1 diabetes was studied. To that end the urinary excretion rates of albumin and Tamm-Horsfall protein as well as HbA1c levels were measured in 58 patients with different degrees of diabetic nephropathy and in 76 apparently healthy subjects matched for sex and age. The urinary Tamm-Horsfall protein levels were measured by a simplified enzyme linked immunoassay. The intra- and interassay variations were 8.9% and 13.6%, respectively. The intraindividual variation was 41% and the sensitivity of the assay was 4 micrograms/l. The Tamm-Horsfall protein excretion rate was 42.1 x/2.0 micrograms/min (geometric mean x/tolerance factor) in the diabetic patients compared to 34 x/1.9 micrograms/min in the control subjects (NS). The diabetic patients had higher albumin excretion rate (38.5 x/7.3 micrograms/min) than the control subjects (4.7 x/2.3 micrograms/min; P less than 0.001). By using multivariate analysis of variance, HbA1c level was found to be the only independent variable associated with Tamm-Horsfall protein excretion rate in diabetic patients (r = -0.28; P = 0.04), while no relationship was found between Tamm-Horsfall protein excretion rate and age, age at onset and duration of diabetes, gender, serum creatinine, diuresis, urinary albumin excretion rate, systolic and diastolic blood pressure levels and antihypertensive treatment. The urinary albumin excretion rate was associated with diastolic blood pressure (r = 0.34; P = 0.02) but not with HbA1c levels when testing the above variables by multivariate analysis of variance. In conclusion, these results may indicate a lack of relationship between glomerular and tubular dysfunction. The former was influenced only by diastolic blood pressure levels and the latter only by the degree of metabolic control. However, the correlations were weak and do not provide any insight into what is actually responsible for glomerular and tubular dysfunction.     

Clinical practice guidelines for chronic kidney disease in adults: Part II. Glomerular filtration rate, proteinuria, and other markers

The Kidney Disease Outcome Quality Initiative of the National Kidney Foundation published clinical practice guidelines on chronic kidney disease in February 2002. Of the 15 guidelines, the first six are of greatest relevance to family physicians. Part II of this two-part review covers guidelines 4, 5, and 6. Glomerular filtration rate is the best overall indicator of kidney function. It is superior to the serum creatinine level, which varies with age, sex, and race and often does not reflect kidney function accurately. The glomerular filtration rate can be estimated using prediction equations that take into account the serum creatinine level and some or all of specific variables (age, sex, race, body size). In many patients, estimates of the glomerular filtration rate can replace 24-hour urine collections for creatinine clearance measurements. Urine dipsticks generally are acceptable for detecting proteinuria. To quantify proteinuria, the ratio of protein or albumin to creatinine in an untimed (spot) urine sample is an accurate alternative to measurement of protein excretion in a 24-hour urine collection. Patients with persistent proteinuria have chronic kidney disease. Other techniques for evaluating patients with chronic kidney disease include examination of urinary sediment, urine dipstick testing for red and white blood cells, and imaging studies of the kidneys (especially ultrasonography). These techniques also can help determine the underlying cause of chronic kidney disease. Family physicians should weigh the value of the National Kidney Foundation guidelines for their clinical practice based on the strength of evidence and perceived cost-effectiveness until additional evidence becomes available on the usefulness of the recommended quality indicators.     

零点肾穿活检:对供者临床资料与组织学异常情况的相关性分析

背景:目前,活体肾脏捐赠的数量在全国乃至全世界范围内增长,因此,保障供者安全在亲体肾移植中占有重要地位.如何准确诊断移植供者可能存在的肾脏疾病,以指导供者手术后潜在肾脏病治疗和肾功能保护成为亲体肾移植后保障供者安全的重要课题.目的:建立一种对供者捐肾前的临床资料与组织学异常情况间相关性的评价方法.方法:对解放军南京军区福州总医院2008-02/2009-11所有亲属肾移植的相关数据做回顾件分析,于供肾血管离断并灌注完成后进行穿刺.用零点肾穿的方法评估下列病变:间质纤维化,小管萎缩,微小动脉透明变性,肾小球系膜增生和肾小球硬化.移植前的统计数据包括:体质量,体质量指数,收缩压,舒张压,血清肌酸酐,肾小球滤过率和蛋白尿.结果与结论:62例供者术前检查均未发现明显肾脏疾病征象,零点肾穿活检发现肾脏病理改变28例,其中间质纤维化与收缩压和肌酐清除率,肾小管萎缩与舒张压和尿蛋白,小动脉透明样变与肌酐和肾小球滤过率,肾小球系膜增生和体质量指数具有弱相关性,肾小球硬化与其他变量均无相关性.     

血清胱抑素C测定对糖尿病肾病早期诊断的临床意义

目的研究血清胱抑素C在2型糖尿病肾病早期诊断中的临床应用。方法收集115例2型糖尿病患者,根据24小时尿白蛋白排泄量,将患者分为单纯性糖尿病组、早期DN组、临床DN组。比较三组患者血清胱抑素C、血肌酐、肾小球滤过率、肌酐清除率检测出。肾功能异常的比例并分析血清胱抑素c与肾小球滤过率的相关性;根据肾小球滤过率的数值,将单纯性糖尿病组的患者分为eGFR％60ml／min／1．73m^2和eGFR≥60ml／min／1．73m^2组,对两组间血清胱抑素C等各项指标进行比较,进行统计学分析。结果 1.血清胱抑素C与肌酐清除率检出肾功能异常的比例相当,但均明显高于血肌酐及尿素氮。2．在24小时尿白蛋白排泄量〈30mg的患者中,eGFR〈60ml／min／1．73m^2组患者的胱抑素C的水平明显高于eGFR≥60ml／min／1．73m^2的患者。结论血清胱抑素C与肾小球滤过率有很好的相关性,且在正常蛋白尿的糖尿病患者中即可以提示早期肾小球滤过率的下降。     

Role of atrial natriuretic peptide in the increase in glomerular filtration rate induced by a protein meal

1. The increase in glomerular filtration rate after a protein meal is believed to be mediated by hormonal factors. Since natriuresis is often observed after a protein meal, it was postulated that the increase in glomerular filtration rate after a protein meal might be mediated by atrial natriuretic peptide. 2. Subjects were given a low, medium or high protein meal. Fluid intake was controlled so as to avoid significant extracellular fluid volume expansion. It was found that the creatinine clearance, the urea excretion, the fractional sodium excretion and the potassium excretion were elevated in all subjects after protein meals (P less than 0.05). These effects were not observed in subjects given a carbohydrate control meal. 3. The plasma atrial natriuretic peptide concentrations remained unchanged in all subjects except those given a high protein meal (P less than 0.05). There was no significant relationship between plasma atrial natriuretic peptide concentrations and creatinine clearance before or after a protein meal. 4. The data suggest that a high protein meal induces a minor increase in plasma atrial natriuretic peptide concentration, whereas a low or medium protein meal does not. It is unlikely that the change in creatinine clearance after a protein meal can be explained by a change in plasma atrial natriuretic peptide levels.     

Renal excretion of proteins and enzymes in workers exposed to cadmium

The proteinuria rate and the relative clearances of beta 2-microglobulin, orosomucoid, albumin, transferrin and IgG were measured in forty-two workers exposed to cadmium and in seventy-seven control workers. A tubular type proteinuria with an increased excretion of beta 2-microglobulin and often also a glomerular type proteinuria with an increased excretion of orosomucoid, albumin, transferrin and IgG were observed mainly in workers exposed to cadmium for more than 25 years and whose cadmium concentration in blood exceeded 1 microgram Cd/100 ml and that in urine 10 microgram Cd/g creatinine. The glomerular dysfunction was also suggested by an increased plasma level of beta 2-microglobulin and creatinine. Both tubular and glomerular impairments occurred with the same prevalence and were not necessarily associated. The increased release of beta-galactosidase by the kidney suggested that cadmium can damage some epithelial cells.     

Evolution of glomerular filtration rate in proteinuric NIDDM patients

OBJECTIVE: To evaluate, by means of a precise method, the rate of decline of glomerular filtration rate in proteinuric non-insulin-dependent diabetic (NIDDM) patients. RESEARCH DESIGN AND METHODS: The study was comprised of seven NIDDM patients who visited an outpatient clinic and had a 24-h urinary protein excretion rate greater than or equal to 500 mg in the absence of heart failure, urinary tract infection, or other nephropathies. RESULTS: Glomerular filtration rate (51Cr-labeled EDTA, single-injection protocol) and 24-h proteinuria (turbidimetric method) were assessed at periodic intervals (2-6 mo). Correlation of the measurements with time (Pearson's r, with Student's t test used to assess the significance, alpha = 0.05) was used to evaluate the trend of evolution of glomerular filtration rate. Renal biopsies were performed in four patients. In three of four patients, renal histopathology was consistent with the diagnosis of diabetic nephropathy (in the 4th patient measurements were not satisfactory). Neither glomerular filtration rate nor proteinuria correlated significantly with time, except in one patient who had multiple myeloma. CONCLUSIONS: The decline of glomerular filtration rate in proteinuric NIDDM patients is different from that observed in insulin-dependent diabetic patients, which is probably much slower.     

Factors affecting the urinary excretion of albumin in insulin-dependent diabetes

To determine the specificity of the urine excretion of albumin as a measure of glomerular permeability in early insulin-dependent diabetic nephropathy, the effect of variable glomerular filtration and urine flow rates on albumin, beta 2-microglobulin excretion, and the fractional renal clearance of neutral dextran (Stokes Einstein Radius 24-46 A) was examined. Five insulin-dependent diabetic subjects with normal glomerular permeability (albumin excretion less than 30 micrograms/min) and one with elevated albumin excretion (195 micrograms/min) were studied pre and post strict glucose control with constant subcutaneous insulin infusion for 7 days. The albumin excretion in the 5 subjects never exceeded 30 micrograms/min during wide variations in glomerular filtration and urine flow rates. A positive correlation between beta 2-microglobulin excretion and urine flow (r = 0.81), and glomerular filtration (r = 0.77) rates was observed. In contrast, albumin excretion showed no correlation, indicating different factors affect the excretion rate of albumin and beta 2-microglobulin. Therefore, elevated albumin excretion (greater than 30 micrograms/min) in insulin-dependent diabetes is due to increased glomerular permeability and not changes in glomerular filtration and urine flow rates, and the albumin/ beta 2-microglobulin ratio may not be a valid indicator of changing glomerular permeability. The fractional neutral dextran clearances remained unchanged with variation in glomerular filtration and urine flow rates. The sieving curve was identical in all subjects for neutral dextran 40 A, the size of albumin, suggesting that reduced glomerular charge selectivity may contribute to increased albuminuria in progressive diabetic glomerulosclerosis.     

Renal clearance of pancreatic and salivary amylase relative to creatinine clearance in patients with renal disease and proteinuria

To study the charge-selective properties of the glomerular filter in renal disease, we measured the fractional clearance, relative to creatinine clearance (ECC), of the amylase isoenzymes pancreatic amylase and salivary amylase, which have identical size but different charge. In 63 healthy subjects the mean (and SD) fractional excretion of pancreatic amylase, 4.07% (1.24%), was fourfold that of salivary amylase: 1.02% (0.54%). For 29 patients with renal disease and proteinuria, the mean fractional excretion of pancreatic amylase was significantly lower, 3.31% (1.94%), and that of salivary amylase significantly higher, 2.06% (1.41%), than in controls. In these patients, fractional excretions of both these isoenzymes were negatively correlated with urinary excretion of beta 2-microglobulin and ECC. Evidently, differences in clearances of pancreatic and salivary amylase are a consequence of differences in charge-related glomerular filtration. The relative increase of salivary amylase clearance in patients with renal disease and proteinuria is most probably caused by a loss of the charge-selective properties of the glomerular basement membrane.     

Human Tamm-Horsfall glycoprotein: urinary and plasma levels in normal subjects and patients with renal disease determined by a fully validated radioimmunoassay

A recently developed, simple and sensitive radioimmunoassay has been used to examine 24 h excretion and plasma levels of Tamm-Horsfall glycoprotein (THG) in normal subjects, stone formers and patients with stable chronic renal disease. In normal subjects THG excretion ranged from 22 to 66 mg/24 h, with no sex difference and no correlation with creatinine clearance or body surface area. There was no correlation between 24 h THG excretion and urine volume, pH or osmolality, excretion of Na+, K+ or Ca2+ or free-water clearance. There was a small significant correlation between plasma THG concentration and urinary THG excretion. A good correlation was obtained between the THG/creatinine ratio in 24 h and random samples. This made possible the use of random samples to establish a reference range for THG excretion of 0.15-0.50 micrograms/ml of creatinine clearance which did not depend on sex or age. The excretion rate of THG in stone formers was generally within the reference range. It was not significantly different in those who were hypercalciuric or in those taking thiazides. In patients with chronic renal disease there was a good correlation between 24 h THG excretion, plasma THG concentration and creatinine clearance. The range of excretion of THG per ml of creatinine clearance was greater than in normal subjects, independent of the type of renal disease and unrelated to proteinuria. In patients with glomerulonephritis the excretion of THG per ml of creatinine clearance was significantly higher in those with well-preserved tubules compared with those with tubular atrophy.     

Large scale clinical trials in prevention of end-stage renal disease due to type 2 diabetes with angiotensin receptor antagonists

Abundant data from studies of patients with proteinuric nephropathy confirm that angiotensin-converting-enzyme(ACE) inhibitors slow the progression of kidney disease more effectively than many other medications. Three studies, RENAAL, IDNT, and IRM2 provide additional evidence with regard to this issues. In IDNT, two doses of irbesartan were administered to patients with type 2 diabetes and hypertension who had normal glomerular filtration rate. The diminution of proteinuria indicates protection from ongoing kidney damage that would probably translate into the preservation of the glomerular filtration rate in the longer term. In RENAAL and IRM2 patients who had higher grade proteinuria and established renal insufficiency were enrolled. In patients whose disease was at this more advanced phase, losartan or irbesartan led to lower levels of proteinuria, lower rates of decline in the glomerular filtration rate, and later onset of end-stage renal disease than the control medications, amlodipine and a mixture of drugs. Moreover, these beneficial effects are independent of the reduction in blood pressure.     

Urinary alpha 1 microglobulin levels in surveys of Balkan endemic nephropathy

The urinary alpha 1-microglobulin (alpha 1m) concentration was measured in 644 adults living in districts where Balkan nephropathy (BEN) is endemic. Comparison of alpha 1m with other indicators of tubular proteinuria, which is a classical sign of BEN, showed alpha 1m was a satisfactory marker. Using a cut-off of 20 mg alpha 1m/L none of 102 normal UK residents had a positive level. Whilst a raised level of alpha 1m was present in 85.7% of definitive cases of BEN and in 8.1%, 10.2% and 50% of subjects previously classified as normal, at risk and suspicious respectively according to the criteria used for epidemiological surveys of BEN.     

同一医院5年期间活体供肾摘取后供者孤肾功能变化117例分析

目的:通过在活体供肾摘取后对供者孤肾功能进行全面性、规律性、连续性地评估,了解供者孤肾在活体供肾摘取后的功能变化,从而分析活体供肾摘取的临床可行性.方法:选择亲属活体肾移植供者117例,肾摘取后通过连续监测血清肌酐水平、肾小球滤过率、尿常规及血压水平等各项指标,并在出院后坚持随访,全面评估供者孤肾在活体供肾摘取后的变化及供者的全身健康状况.结果:117例活体供肾患者均顺利接受手术,其中2例肾摘取后围手术期出现药物过敏反应;8例肾摘取后尿常规镜检有红细胞;5例出现微量蛋白尿;15例出现尿路感染;3例围手术期出现情绪焦虑,对自身健康状况表示担心;22例围手术期出现切口疼痛或不适;19例出现血压轻度增高,但均在正常血压范围内.所有供者肾摘取后均出现肾小球滤过率的下降,下降4～25 mL/min,平均(9.4±4.7) mL/min,均未超出正常肾小球滤过率范围.所有供者肾摘取后均出现血清肌酐升高,43例在供肾后2个月时仍超过正常水平;在肌酐增长水平与肾小球滤过率下降程度的比较中,左侧与右侧孤肾、男性与女性供者间差异均无显著性意义;但50岁以上供者肌酐水平高于50岁以下供者(P < 0.01).所有患者经对症治疗后各项指标均恢复正常,除外5例肌酐水平至今仍异常,但均稳定在135 μmol/L以内.结论:供者孤肾在活体供肾摘取后各项监测指标均有不同程度变化,甚至在短期内超出正常水平,但这些指标变化并不影响孤肾的整体功能,不影响供者的整体健康状况,从临床角度分析,活体供肾移植是安全可行的.     

Differential effects of atrial natriuretic peptide and dopamine on urinary protein excretion in chronic glomerulonephritis.

1. To examine whether or not atrial natriuretic peptide-induced proteinuria simply results from increases in urine flow or glomerular filtration rate, we infused dopamine (1 microgram min-1 kg-1) and alpha-human atrial natriuretic peptide (0.025 microgram min-1 kg-1) into nine patients with chronic glomerulonephritis and nine essential hypertensive patients without renal damage, and compared the effects of the two agents on renal function and urinary protein excretion. 2. In patients with chronic glomerulonephritis, dopamine infusion significantly increased urinary sodium excretion (+59%), renal blood flow (+20%) and creatinine clearance (+14%). However, urinary protein excretion was not changed. Addition of atrial natriuretic peptide to the dopamine infusion further increased urinary sodium excretion and maintained creatinine clearance at the same level. In contrast to the infusion of dopamine alone, atrial natriuretic peptide markedly increased urinary protein excretion (77 versus 229 mg min-1 m2, P less than 0.02). Furthermore, the addition of atrial natriuretic peptide elevated the urinary protein/creatinine ratio (1.55 versus 5.35, P less than 0.05), while dopamine alone did not (1.55 versus 1.45, not significant). 3. In essential hypertensive patients, dopamine and dopamine plus ANP showed renal effects similar to those of chronic glomerulonephritis; however, the urinary excretion of protein was not changed significantly. 4. These results suggest that atrial natriuretic peptide may increase urinary protein excretion mainly by increasing the permeability of the damaged glomeruli to protein rather than by simply increasing urine flow or glomerular filtration. Possible mechanisms underlying the proteinuria-increasing effects of atrial natriuretic peptide are discussed.     

Use of Paricalcitol as Adjunctive Therapy to Renin-Angiotensin-Aldosterone System Inhibition for Diabetic Nephropathy: A Systematic Review of the Literature

PurposeDiabetic nephropathy (DN) is a major complication of diabetes. Paricalcitol is a vitamin D analog that is typically used for secondary hyperparathyroidism in patients with chronic kidney disease but may have some beneficial effect on DN. This review evaluates the effect of paricalcitol in combination with renin-angiotensin-aldosterone system inhibitor therapy in managing DN.MethodsA literature search was conducted of PubMed and ClinicalTrials.gov. Limits were set to include only clinical trials in humans written in English. The search terms used were paricalcitol and diabetic nephropathy. The following outcomes of kidney function and damage as well as adverse drug events were assessed and included: 24-h urine albumin excretion, serum phosphorus and calcium concentrations, urinary albumin excretion rates, estimated glomerular filtration rate, and markers of inflammation and endothelial function.FindingsFour studies with a total of 389 patients were identified for review through the process described above. Two of the 6 studies provide evidence of the effect of paricalcitol on DN by way of reduction in urine albumin to creatinine ratio and urinary albumin excretion rate when compared with placebo. One study reported an increase in serum phosphorous, 1 study observed a decrease in estimated glomerular filtration rate, and 1 study reported no effect on inflammatory markers or endothelial function.ImplicationsThe number of clinical trials examining the effect of paricalcitol in DN is small. The studies that have been completed enrolled <300 patients. Paricalcitol can reduce protein in the urine, but there is no compelling evidence that it preserves kidney function.     

The changing face of newborn screening: diagnosis of inborn errors of metabolism by tandem mass spectrometry

BACKGROUND: The concentration of serum cystatin-C (Cys-C) is highly correlated with creatinine (Cr), and is mainly determined by glomerular filtration; thus, Cys-C may be an index of the glomerular filtration rate (GFR). However, the kinetics of urinary Cys-C and Cr excretions are unclear. Thus, we investigated the kinetics of urinary Cys-C and Cr excretions, and examined whether the urinary Cys-C concentration can be used as a marker of renal function. METHODS: The urinary excretion of Cys-C and Cr was evaluated in 1670 healthy subjects and 217 patients with proteinuria. We also investigated the urinary Cys-C concentration in 52 patients with chronic renal failure. RESULTS: There was a good correlation between the urinary concentrations of Cys-C and Cr in the healthy group. This relation was also observed in patients showing persistent proteinuria without tubular cell damage. The mean urinary Cr concentration increased with age, and it was affected by the muscle mass. In contrast, the urinary Cys-C concentration was not affected by the muscle mass, and the concentration remained constant for all ages. We further found that the ratio of Cys-C to Cr (CCR) is a good index of the state of Cys-C reabsorption in the proximal tubules. CONCLUSIONS: The urinary CCR can be a marker of renal tubular dysfunction. In addition, when CCR was in the normal range, the urinary Cys-C concentration accurately reflected the glomerular filtration function.