Dose effect of nitrendipine on urinary enzymes and microproteins following non-ionic radiocontrast administration

BACKGROUND.: Although calcium-channel antagonists have been proposed as prophylaxisto prevent radiocontrast-induced nephropathy, the dose and doseinterval to achieve a protective effect have not been quantifiedin humans. METHODS.: In a randomized, double-blind protocol we studied urinary enzymeand microprotein excretion in 121 outpatients (mean age 65.3±9.3 years, 62% male) with normal renal function whowere to undergo digital subtraction arteriography with iohexolor iopentol. The subjects were treated with a single dose ofplacebo (group 1) or nitrendipine 10 mg (group 2) or 20 mg (group3) p.o. 1 h before the procedure. Blood and urine samples werecollected 1 h before, 1 h after, and 24 h after contrast administration.Study variables included contrast volume and serum creatinine,and urinary creatinine, osmolality, albumin, alanylaminopeptidase(AAP, a brush border enzyme), N-acetyl-ß-glucosaminidase(NAG, a lysosomal enzyme), and -1-microglobulin (-1-micro, afiltered microprotein). RESULTS.: Serum values of creatinine remained unchanged during the studyperiod. Albuminuria was not affected by contrast administration,whereas AAP, NAG, and -1-micro increased significantly, allexcept AAP returning to baseline at 24 h. Pretreatment withnitrendipine did not reduce enzyme excretion, although AAP levelswere lower in general in the group assigned to the 20-mg dose.Acute renal failure, defined as a 50% increase of serum creatinine24 h after radiocontrast administration, was found in eightpatients: four from group 1 (8.3%), three from group 2 (6.5%),and one from group 3 (3.7%). CONCLUSIONS.: Neither the course of enzyme excretion nor the incidence ofacute renal failure following radiocontrast administration wereaffected by single doses of calcium antagonists. AAP levelswere lower in general in subjects taking the 20-mg dose of nitrendipine.This study also indicates that a single low or normal dose ofnitrendipine per os is not effective prophylaxis before radiocontrastadministration. The designs of future studies investigatingthe ‘nephroprotective’ effect of calcium-channelantagonists per os should incorporate (1) the use of repeateddoses to saturate hepatic metabolic pathways, and (2) the controlof confounding variables in the measurement of urinary enzymes.     

Nephron target sites in chronic exposure to lead

With established urinary markers of kidney integrity the earlyrenal effects of lead have previously been considered to bemainly tubular or tubulointerstitial. In a cross-sectional studyon 81 male lead-exposed workers and 45 age-matched controls(median blood lead concentrations 2.03 and 0.34 µmol/lrespectively) not only well-established but also new urinarymarkers of renal integrity preferentially or exclusively locatedalong the different nephron segments were analysed. Markersrelated to the glomerulus were 6-ketoprostaglandin₁, thromboxaneB₂ mainly produced in the glomerulus, and the extracellularmatrix protein fibronectin. Markers of the proximal tubule werethe brush-border antigens BBA, BB50, and HF5 and the intestinalalkaline phosphatase. Prostaglandin E₂ and F₂, preferentiallysynthesized in the collecting duct and medullary interstitialcells, served as markers of these more distal nephron segments.In contrast to previous studies on the early phase of lead nephrotoxicity,not only tubular but also glomerular involvement could be shownin the study presented here by increases in the median valuesof 6-keto-prostaglandin₁, and decreases in fibronectin. Theproximal tubular markers intestinal alkaline phosphatase andBBA confirmed that this particular segment of the nephron isaffected by lead. Effects on the collecting tubule or medullaryinterstitial cells could also be observed. It is concluded thatlead affects both the glomerulus and the tubular apparatus andthat combinations of new and established markers could be valuablefor a better definition and early detection of lead nephropathy.     

Increased urinary excretion of orosomucoid is a risk predictor of diabetic nephropathy

Aim:   Identification of the risk predictor of diabetic nephropathy (DN) remains a major challenge currently. Thus, proteomic approaches to identify DN-related biomarker were performed.
Methods:   A comparative proteomic approach of 2-D gel electrophoresis (2-DE) and mass spectrometry to identify biomarkers in urine samples from 12 DN patients (six type 1 and six type 2 diabetic patients) and six healthy controls. Then, the urinary level of identified protein biomarker was detected by immunoturbidimetry assay in urine samples from 90 type 1 and type 2 diabetic patients with normo-, micro- and macroalbuminuria ( n  = 30 in each group), and 30 healthy controls.
Results:   A novel DN-related protein, orosomucoid (α1-acid glycoprotein), was identified by proteomic method. Its abundance was highly upregulated (>eightfold) in DN patients. The data of immunoturbidimetry assay showed urinary orosomucoid excretion rate (UOER) was gradually increased in the normo-, micro- and macroalbuminuria group versus control (0.71 ± 0.41, 1.93 ± 0.68, 2.88 ± 0.94 vs 0.39 ± 0.28 ug/min, P  < 0.05). The result indicated that UOER increased in early stage of DN and gradually increased with the development of DN. Also, Pearson's correlation analysis indicated UOER was positively correlated with urinary albumin excretion rate, serum creatinine and C-reactive protein ( r  = 0.830, 0.787 and 0.360, respectively; P  < 0.05). Multivariate logistic regression analysis also showed that increased UOER was an independent risk factor for DN (odds ratio = 3.10, P  < 0.0001).
Conclusion:   Urinary orosomucoid is a DN-related biomarker, which is associated with the development and progression of DN. Furthermore, increased UOER is an independent risk factor of DN.     

The effect of triathlon on urinary excretion of enzymes and proteins

In order to investigate the effect of triathlon and renal function of normal subjects, we evaluated the excretion of urinary enzymes and proteins before and after triathlon. From 6 subjects samples were obtained 24 hours after the first urine collection. We performed quantification of urinary total protein, β₂-microglobulin (β₂-M), N-acetyl-β-D-glucosaminidase activity (NAG), and concentration of urinary creatinine from each participant. There was a significant increase in urinary total protein excretion immediately after triathlon (p<0.01). The urinary β₂-M and NAG excretions after triathlon were higher than the initial values. Post-exercise proteinuria in one subject persisted until the next morning, whereas the increased excretion of urinary β₂-M and NAG returned to the pre-exercise level at least 24 hours after triathlon. It appears to be reasonable to presume that glomerular damage may persist in some subjects who do heavy exercise.     

Therapy with atorvastatin versus rosuvastatin reduces urinary podocytes,podocyte-associated molecules,and proximal tubule dysfunction biomarkers in patients with type 2 diabetes mellitus: a pilot study

Background: Diabetic nephropathy is a severe complication of Type 2 diabetes. Tubular lesions may play an important role in its early stages. The aim of our study was to determine if atorvastatin protects the podocytes and the proximal tubule in patients with Type 2 diabetes.

Methods: A total of 63 patients with Type 2 diabetes completed this 6-months prospective pilot study. They were randomized to continue rosuvastatin therapy (control group) or to be administered an equipotent dose of atorvastatin (intervention group), and were assessed regarding urinary podocytes, podocyte-associated molecules, and biomarkers of proximal tubule dysfunction.

Results: The patients from the intervention group presented a significant reduction in podocyturia (from 7.0 to 4.0 cells/ml, p?p?p?1-microglobulin (from 10.0 to 8.3?mg/g, p?p?p?Conclusions: In patients with Type 2 diabetes, atorvastatin exerts favorable effects on the kidney. There is a correlation between the evolution of the podocytes and of the proximal tubule biomarkers, supporting the hypothesis that the glomerular changes parallel proximal tubule dysfunction in the early stages of diabetic nephropathy.     

Treatment-related changes in urinary excretion of high and low molecular weight proteins in patients with idiopathic membranous nephropathy and renal insufficiency.

BACKGROUND: In patients with idiopathic membranous nephropathy, an increased urinary excretion of high (IgG) and low [beta(2)-microglobulin (beta(2)M), alpha(1)-microglobulin (alpha(1)M)] molecular weight proteins predicts prognosis and precedes renal insufficiency. We have studied the changes in the urinary excretion of these proteins in patients with idiopathic membranous nephropathy and renal insufficiency during and after treatment with cyclophosphamide and steroids, and investigated their value in predicting long-term outcome. METHODS: Standardized measurements of urinary IgG, albumin, beta(2)M and alpha(1)M were performed at 0, 2, 6 and 12 months in 11 patients, at 12 months in 25 patients and in 17 of these last patients after 2-5 years. RESULTS: We observed a rapid improvement of glomerular permselectivity and tubular protein reabsorption within 2 months after the start of therapy. Despite a partial remission of proteinuria within 12 months in most patients, evidence of tubulo-interstitial injury remained apparent. Neither absolute levels of urinary IgG, beta(2)M or alpha(1)M at baseline or at 12 months nor the percentage reduction between baseline and 12 months clearly predicted the occurrence of a remission or a relapse to nephrotic range proteinuria. In the case of a persistent stable remission, we observed a gradual decrease of urinary beta(2)M towards normal values. CONCLUSIONS: In patients with idiopathic membranous nephropathy and renal insufficiency, treatment with cyclophosphamide and steroids resulted in an improvement of glomerular permeability and tubular proteinuria. Tubular proteinuria remained present for many years, even in patients with stable remission of proteinuria. Measurements of urinary proteins at 12 months after treatment start lacked predictive accuracy.     

Differential excretion of urinary proteins in children with vesicoureteric reflux and reflux nephropathy

We studied 40 children with a history of vesicoureteric reflux (VUR) without evidence of renal scarring, 93 children with a history of VUR and renal scarring and 10 children with previous urinary tract infections in whom the urinary tract was radiologically normal. Urine retinol-binding protein (RBP), albumin andN-acetyl--d-glucosaminidase (NAG) were measured in each child. All were free from infection at the time of the analysis. Urinary RBP and NAG levels were significantly elevated (P<0.001) in the group of children with renal scarring. Elevated RBP levels were detected in 51% of children with bilateral renal scarring compared with 7% of children with unilateral scarring. Urine RBP excretion increased progressively according to the type of scarring, best determined by the type of scarring of the less affected kidney. In children with renal scarring, elevated NAG levels were seen mostly in the 65 children with bilateral scarring and severe reflux. Urine albumin excretion was elevated in 10 children, 9 with bilateral scarring, all of whom had elevated RBP excretion. Urine protein excretion was unaffected by the presence or absence of persisting VUR. There was a strong negative correlation between glomerular filtration rate and RBP excretion (r=–0.69). We conclude that evidence of tubular dysfunction is common in children with bilateral renal scarring and usually precedes any glomerular protein leak. Tubular dysfunction may be the consequence of relative nephron hyperperfusion in the presence of bilateral scarring.     

Effect of ethyl icosapentate on urinary calcium and oxalate excretion

BACKGROUND: The effect of ethyl icosapentate (EPA-E) on urinary calcium and oxalic acid excretion was examined to evaluate whether EPA-E is useful in the prevention of calcium-containing urinary stones. METHODS: For 6 months, urine was measured daily from 40 calcium-containing urinary stone producers at an outpatient clinic, before and after the administration of 1800 mg/day EPA-E. The urine was measured for volume, urea nitrogen, creatinine, calcium, magnesium, phosphorus, uric acid, oxalic acid and citric acid. Serum total cholesterol and triglyceride were also measured. RESULTS: Urinary calcium excretion was not reduced in any of the patients or particular hypercalciuric groups, nor did the level of calcium change. However, nine of the 25 hypercalciuric patients experienced a significant urinary calcium reduction to the normal calciuric level (a reduction of approximately 44%). It is not known why these particular patients experienced a reduction. Urinary oxalic acid did not change, whether hypercalciuria was present or not. CONCLUSIONS: These findings suggest that EPA-E is not particularly effective in reducing urinary calcium excretion in the hypercalciuric patients, but it needs future investigation because some patients experienced significant urinary calcium reduction.     

血浆降钙素原对于复杂性上尿路感染导致尿脓毒血症的预警作用研究

目的:探讨血浆降钙素原(PCT)水平变化在复杂性上尿路感染患者病情进展为尿脓毒血症的预警作用。方法:回顾性分析我院2012年1月~2013年11月收治的98例上尿路结石合并复杂性上尿路感染患者,患者均接受上尿路结石手术治疗,并分别在手术治疗前及术后第1天测定血浆PCT及C反应蛋白(CRP)。参照2011版《中国泌尿外科疾病诊断治疗指南》对接受手术治疗后出现临床细菌感染症状并伴发全身炎症反应综合征(SIRS)的患者诊断为尿脓毒血症,按照患者在手术治疗后是否并发尿脓毒血症分为观察组和对照组,对观察组和对照组患者的血浆PCT水平差异进行统计学分析处理。结果:纳入本研究共98例患者中,手术治疗后并发尿脓毒血症(观察组)共48例,手术治疗后未并发尿脓毒血症(对照组)共50例,经过对两组患者不同阶段血浆PCT水平及C反应蛋白水平的差异进行统计学分析,两组间手术治疗前血浆PCT水平差异无统计学意义(P0.05),术后第1天两组血浆PCT水平较术前均升高,观察组术后第1天血浆PCT水平较术前明显升高,差异具有统计学意义(P0.05),对照组术后第1天血浆PCT水平较术前升高,统计显示差异具有统计学意义(P0.05),两组术后第1天血浆PCT水平比较,差异具有统计学意义(P0.01)。结论:上尿路结石合并复杂性上尿路感染患者在接受手术治疗后,测定术后第1天血浆PCT水平可作为是否会并发尿脓毒血症的预警指标。     

Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis

SUMMARY:   Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin II, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na⁺ reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as 'protein metabolic overload hypothesis'. Impaired metabolism of bioactive proteins such as angiotensin II and insulin in PTC may enhance hypertrophy of PTC and/or Na⁺ reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.     

复发性泌尿系结石患者24h尿枸橼酸盐含量的病例对照研究及结石成分分析

目的:分析复发性泌尿系结石患者尿枸橼酸排泄量与结石成分及微观形态,探讨泌尿系结石形成与复发的防治措施。方法:采用病例对照的研究方法,比较复发性泌尿系结石患者与对照组之间的尿枸橼酸排泄量,并运用红外光谱、X线衍射及扫描电镜分析复发性结石的成分与微观形态。结果:复发性结石患者尿枸橼酸排泄量显著低于对照组。结石的成分以草酸钙(80%)和尿酸结石(33%)为主。结论:结石患者术后的代谢分析、严格随访和适量的枸橼酸盐补充,可能在一定程度上降低泌尿系结石的复发率。泌尿系结石的成分分析可为制定预防结石复发方案提供理论依据。     

氟伐他汀对糖尿病肾病大鼠足细胞分布及排泄的影响

目的探讨氟伐他汀对DN大鼠足细胞分布及排泄的影响。方法将大鼠分为3组：对照组、DN模型组、氟伐他汀治疗组。腹腔注射链脲菌素（STZ）诱导DN大鼠模型。实验10周末测24小时尿蛋白定量（TP）、血清总胆固醇（TC）,间接免疫荧光法检测尿沉渣足细胞特异性标志蛋白podocalyxin（PCX）以检测尿液足细胞（UPC）水平;免疫荧光染色观察肾小球上皮细胞蛋白-1（GLEPP1）的分布。结果DN模型组UPC、TP、TC较对照组均明显升高;氟伐他汀治疗组TC、UPC及TP较DN模型组均降低;对照组GLEPP1正常、DN模型组呈节段性明显缺失、氟伐他汀治疗组缺失较轻。UPC与TP呈正相关,与TC无显著相关性。结论尿液中脱落足细胞检测可作为判断DN病情活动性的标志之一。氟伐他汀可减轻DN大鼠尿蛋白、降低胆固醇、减少足细胞脱落及排泄。     

Management of polyuria subsequent to pituitary surgery based on the diurnal pattern of urinary excretion

Polyuria subsequent to pituitary surgery was studied in 64 cases. Most cases of postoperative polyuria were due to diabetes insipidus. These cases showed a triphasic pattern in daily urinary volume. Observation of hourly urinary volume in polyuria revealed four diurnal patterns of urinary excretion: rhythmic, continuous, transient, and unspecific. Clinical observation of diurnal patterns has an advantage, in terms of simplicity of procedure, in immediately determining the nature of the polyuria, prognosticating diabetes insipidus, and eliminating inappropriate procedures in treatment. Indomethacin suppository is considered to be a favorable agent in reducing polyuria without disturbing the diurnal pattern in diabetes insipidus.     

Acute effects of acetaminophen on renal function and urinary excretion of some proteins and enzymes in patients with kidney disease.

The acute effects of acetaminophen, a commonly used as analgesic drug, upon the urinary excretion of some proteins and enzymes as markers of kidney damage, was investigated. Patients with chronic glomerulonephritis (GN) and Balkan endemic nephropathy (BEN), having kidney vulnerable to toxic drugs, were enrolled in the study. Timed urine specimens were collected: before drug administration, and in 3-hour periods for 24 hours after an oral dose of 2 g of acetaminophen. Urinary excretion of albumin before acetaminophen treatment was significantly higher in patients with GN and BEN than in healthy adults, however, beta 2-microglobulin excretion was increased in BEN patients only. Urinary excretion of creatinine markedly increased immediately after acetaminophen ingestion. Urinary excretion of total protein and albumin was not changed after acetaminophen administration. However, acetaminophen treatment produced a significant increase in beta 2-microglobulin excretion in patient with BEN and GN, and in clinically healthy members of nephropathic families. Excretion of aminopeptidase N (APN) activity before acetaminophen treatment was significantly higher in patients with GN, however, NAGA excretion was higher in both GN and BEN patients than in healthy controls. After acetaminophen administration urinary excretion of APN, dipeptidylpeptidase IV (DPP IV), gamma-glutamyltranspeptidase (GGT) and N-acetyl-beta-D-glucosaminidase (NAGA) did not increase significantly in any group studied. This study has shown that urinary excretion of APN, DPP IV, NAGA and GGT, as markers of kidney brush border and lysosomal damage, did not change after 2 g of acetaminophen taken orally. beta 2-microglobulin was a marker of acute acetaminophen nephrotoxicity in kidney disease patients and in clinically healthy adults from nephropathic families.     

Dissociation between urine osmolality and urinary excretion of aquaporin-2 in healthy volunteers.

BACKGROUND: It has been suggested that urinary excretion of the vasopressin-dependent water channel of the kidney collecting duct, aquaporin-2 (AQP2), reflects renal vasopressin action and might be used clinically. It is unclear, however, what relation exists between urine osmolality and urinary excretion of AQP2 (UAQP2) and it is unknown whether UAQP2 is influenced by hyperosmolality of urine or tubular flow rates. METHODS: We measured urine osmolality and UAQP2 in healthy volunteers in various conditions: (i) overnight dehydration continued during the day, (ii) after infusion of 700 ml hypertonic saline (NaCl 2.5%), and (iii) after intranasal administration of 40 microg 1-desamino-8-D-arginine vasopressin (DDAVP). The last two tests were performed after water loading. In addition, a DDAVP test was performed, after administration of frusemide. RESULTS: After overnight dehydration, the urine osmolality increased from 888+/-18 to 1004+/-17 mosmol/kg during additional hours of thirsting, whereas UAQP2 doubled from 140+/-45 to 285+/-63 fmol AQP2/micromol creatinine. Infusion of hypertonic saline increased urine osmolality from 70+/-3 to 451+/-68 mosmol/kg, while UAQP2 remained almost zero. Urine osmolality increased from 101+/-17 to 860+/-30 mosmol/kg after administration of DDAVP, with a parallel increase in UAQP2 from 32+/-14 to 394+/-81 fmol AQP2/micromol creatinine. Pre-treatment with frusemide attenuated the increase in urine osmolality, but had no effect on UAQP2 after DDAVP. CONCLUSIONS: Our data demonstrate that a simple relationship between urine osmolality and UAQP2 does not exist. Therefore, random or once-only measurements of UAQP2 as an index of renal vasopressin action are not useful. In contrast, intranasal application of DDAVP resulted in a parallel rise in urine osmolality and UAQP2. Therefore this test might be useful in studying patients with urine concentration defects. The DDAVP-frusemide test revealed that the release of AQP2 into urine is not caused by hypertonicity of tubular fluid.     

Radiocontrast-induced nephrotoxicity and urinary alpha-glutathione S-transferase levels: Effect of amlodipine administration

AIMS: The exact pathogenesis and prophylaxis concerning radiocontrast-induced nephrotoxicity (RCIN) was unclear. Short-acting calcium antagonists were used to prevent RCIN. This study was designed to evaluate the role of a long-acting calcium antagonist (amlodipine) administration by determining serum creatinine (SCre) levels and 24 hour urinary excretion rates of glutathione S-transferase alpha (GST-alpha) which has a selective localization only to proximal tubular epithelium. METHODS: In a prospective trial, 29 outpatients (19 M, 10 F) undergoing coronary angiography were randomized and either amlodipine 10 mg/day (n = 15) or placebo (n = 14) were administered prior to angiography and continued thereafter. All patients had normal basal renal function and none of them had any risk factor for RCIN. A low osmolar, nonionic contrast media (iopamidol 76%) was administered to all patients. Creatinine clearance (CCre), SCre and 24-hour urinary GST-alpha levels were measured before, 24 hours and 7 days after angiography. RESULTS: SCre and 24 hour urinary GST-alpha values increased on 24th hour following the angiography in both groups (p < 0.017 and 0.001, respectively). Pretreatment with amlodipine created no difference in both variables (p > 0.05). CONCLUSIONS: A reversible tubular dysfunction occurs following radiocontrast administration which was manifested by an increase in urinary GST-alpha excretion rates. Pretreatment with a long acting calcium antagonist amlodipine has no effect on the course of enzyme excretion and alteration observed in SCre.