Indicator Of Renal Tubular Damage Research Articles

The Clinical Significance of Urinary Retinol-Binding Protein 4: A Review.

Effective biomarkers for early diagnosis, prognostication, and monitoring in renal diseases (in general) comprise an unmet need. Urinary retinol-binding protein 4, which is the most sensitive indicator of renal tubular damage, holds great promise as a universal biomarker for renal pathologies, in which tubular injury is the driving force. Here, we summarize the most important existing data on the associations between urinary retinol-binding protein 4 and renal diseases and highlight the untapped potential of retinol-binding protein 4 in clinical use.

Fractional excretion of magnesium as an early indicator of renal tubular damage in normotensive diabetic nephropathy

Abstract Objectives The aim of the present study is to evaluate the diagnostic powers of fractional magnesium, sodium and potassium as markers of renal tubular damage in normotensive type 2 diabetes mellitus (T2DM) patients with respect to microalbuminuria and estimated glomerular filtration rate (eGFR). Materials and methods Forty healthy volunteers and 91 normotensive T2DM patients were included in the study. Patient group was divided into two according to albuminuria level; 49 were normoalbuminuric and 42 were microalbuminuric. In addition to albumin in urine, urine and serum Na, K, Mg and creatinine values were measured to calculate fractional electrolyte excretion rates. Results In normoalbuminuric and microalbuminuric groups, fractional excretion of magnesium (FEMg) values were found to be significantly higher than the control group (p < 0.05). There was a moderate correlation between FEMg and albümin to cratinin ratio (ACR) (Spearman r = 0.3215, p < 0.05). In the ROC analysis for eGFR and FEMg based on microalbuminuria, the areas under the curve were 0.625 and 0.732, respectively (diagnostic sensitivity 59.52% and 66.67%; specificity 70.79% and 77.53%, p < 0.05). Conclusion For renal tubular damage predicted by microalbuminuria, FEMg could be accepted as a candidate biochemical marker with diagnostic and prognostic value.

Low level cadmium exposure, renal and bone effects - the OSCAR study

It is well known that high cadmium exposure causes renal damage, osteoporosis and osteomalacia, whereas the dose-response relationships at low-level exposure are less well established. WHO estimated (1992) that a urinary excretion of 10 nmol/mmol creatinine would constitute a 'critical limit' below which kidney damage would not occur. Later, Belgian and Swedish studies have shown signs of cadmium induced kidney dysfunction in the general population already at urinary cadmium levels around 2-3 nmol/mmol creatinine. The Swedish OSCAR (OSteoporosis-CAdmium as a Risk factor) study comprised 1021 individuals, exposed to cadmium in the environment. Blood and urinary cadmium were used as dose estimates. Protein HC (alpha-1-microglobulin) was used as an indicator of renal tubular damage. Forearm bone mineral density (BMD) was assessed with DXA (dual energy x-ray absorptiometry) technique. The study showed that tubular proteinuria occurred at much lower levels of cadmium dose than previously known. A negative dose-effect relationship was found between cadmium dose and BMD for people at the age of 60 or older. In this age group, there was also a dose-response relationship, showing a three-fold increased risk of low BMD in the group with urinary cadmium over 3 nmol/mol creatinine, as compared to the lowest dose group. There was also evidence of an increased risk of forearm fractures with increasing cadmium levels in the population 50 years of age or older. The potential public health consequences of low level cadmium exposure should be recognized, and measures taken to reduce cadmium exposure to an absolute minimum.

Olfactory Function in Workers Exposed to Moderate Airborne Cadmium Levels

Objective: The present study investigated the olfactory function in workers exposed to moderate airborne cadmium (Cd) levels, with the purpose of identifying possible early adverse effects of the metal, not demonstrable with the traditional diagnostic methods. Methods: The exposed group consisted of 33 men employed in cadmium fusion, sintering and alloys lamination. Two reference groups were considered: the first consisted of 39 subjects assigned to manual workings, but not exposed to harmful substances for olfaction (drivers, warehousemen); the second was characterized by 23 subjects exposed to iron and steel welding fumes (iron base alloys), non-specific irritants on the respiratory tract. Olfactory threshold and odor identification ability were separately quantified. Individual occupational exposure was studied by calculating the mean blood and urinary cadmium values (CdB and CdU, respectively) of the five years period during which, for each worker, the highest levels of dose indicators were measured. As indicator of renal tubular damage, urinary β 2-microglobulin levels in the same quinquennium were monitored. Results: Mean olfactory threshold scored significantly higher in Cd workers (−5.26 log 10 v/v, P=0.02) than did in controls (welders: −5.78 log 10 v/v; P=0.26 compared to non-exposed −6.37 log 10 v/v). The odor identification test findings for Cd workers were similar to those of the reference groups. Moderate blood and urine cadmium levels (mean CdB 3.7 μg/l; mean CdU 4.4 μg/g creatinine) accompanied threshold impairment. Olfactory threshold weakening was confirmed in the subgroup of Cd workers in which urinary β 2-microglobulin never exceeded 300 μg/l (−5.41 log 10 v/v; P=0.045 compared to non-exposed). Conclusions: These data suggested that possible early toxic effects of the metal can occur at low levels, close to the limits proposed by the American Conference of Governmental Industrial Hygienists ( ACGIH ®), confirming the hypothesis that primary olfactory neuron may represent the early target for cadmium toxic action. The action of the metal seemed to be due to an elective tropism for the olfactory epithelium and not to a non-specific irritant effect on the nasal cavity. The mechanism of this effect did not appear linearly dose-related. These findings underline the importance of olfactory tests to identify the early effects of xenobiotics even at low-exposure levels, and to contribute to verify the adequacy of the current exposure limits.

Intra individual variability in markers of proteinuria for normal subjects and those with cadmium induced renal dysfunction: interpretation of results from untimed, random urine samples

The project aimed to help interpretation of urinary protein measurements, namely -2-microglobulin, retinol-binding protein, albumin and total protein in untimed, random urine samples as indicating significant changes in renal tubular reabsorption and glomerular permeability in an individual. A standard methodology used in clinical laboratory medicine was applied to calculate the intra-individual biological variation for these analytes. This parameter in conjunction with a laboratory's analytical variation allows definition of uncertainty about a single urine protein measurement, significant changes above normal variation in serial measurements within an individual and a defined level of maximum acceptable analytical imprecision. Repeat urine samples were obtained over a period of one week from a group of cadmium-exposed workers, 90% of whom had long-term tubular proteinuria, and a group of five unexposed volunteers with normal renal function. Dilute samples defined as having creatinines less than 3 mmol l-1 were excluded, as were urines with pH less than 5.5 for -2-microglobulin. Samples were analysed twice after randomisation in large batches. There was no evidence of any diurnal variation in the four protein measurements from samples collected between early morning and 16:00 hours. Creatinine or specific gravity correction of urine results for all four proteins only marginally reduced the uncertainty associated with an individual measurement asreflecting the true excretion value. For those subjects with defined tubular proteinuria, variability in retinol-binding protein excretion was less than that for -2- microglobulin. About 30% of the samples had urine pHs of 5.5 or less where -2- microglobulin degradation occurs. Using our laboratory analytical precision the minimum changes between serial creatinine-corrected measurements that are needed to be considered statistically significant (p < 0.05) is 110% for retinol-binding protein, 177% for -2-microglobulin, 70% for total protein, and 81% for albumin. Unlike published data for cadmium and mercury, the use of creatinine or specific gravity correction of random untimed urine samples for the urinary proteins does not make a large improvement to the interpretation of data by reducing the uncertainty associated with a measurement. There are significant advantages to the use of retinol-binding protein in contrast to -2- microglobulin as an indicator of renal tubular damage. Levels for defined acceptable analytical precision are calculated for laboratories undertaking protein estimations. The data in this report will help in the interpretation of urinary protein measurements without monitoring cadmium workers.

Atividade da gama glutamil transpeptidase urinária, dosagens séricas de uréia e creatinina como meios diagnósticos auxiliares na nefrotoxicidade induzida por aminoglicosídeo em cães

Foram utilizados 11 cães, hígidos, com idade entre 1 e 5 anos. Inicialmente procedeu-se à determinação dos valores basais através de cinco colheitas diárias de urina e sangue, e realizou-se a urinálise, determinação da atividade da gama glutamil transpeptidase urinária, dosagens sérica de uréia e creatinina. A nefrotoxicidade foi induzida com a utilização de10mg/kg de gentamicina, 3 vezes ao dia, durante 14 dias. As colheitas de urina foram realizadas a cada 24 hors e o sangue foi colhido a cada 48 horas, durante 14 dias. Após este período os cães foram submetidos à eutanásia, procedendo-se à necropsia, e estudo histopatológico dos rins. Os sinais clínicos apresentados foram apatia, anorexia, poliúria, oligúria, anúria, polidipsia, vômito e diarréia. Pela urinálise observou-se a ocorrência de proteinúria, glicosúria, hematúria, cilindrúria, celulúria e isostenúria; os valores de gama glutamil transpeptidase urinária elevaram-se de forma crescente a partir de 24 horas de administração da gentamicina até o final do experimento, a azotemia foi observada no 12° e 14° dias da pesquisa. Na avaliação histopatológica observou-se nefrose tubular aguda. Com base nos resultados obtidos pode-se concluir que a mensuração da atividade da gama glutamil transpeptidase urinária é um sensível indicador de lesão tubular renal possibilitando o diagnóstico precoce, juntamente com a urinálise.

The differential diagnostic value of urinary enzyme and amino acid excretion in children with nephrotic syndrome.

Urinary enzymes N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GT) are sensitive markers of specific renal cell damage. Excessive urinary amino acid excretion may also be an indicator of renal tubular damage. We have evaluated urinary excretion of NAG, gamma-GT and 37 amino acids, phospholipids and dipeptides in 30 children (aged 2.3-18.1 years) with nephrotic syndrome (NS), 23 with minimal change nephrotic syndrome (MCNS), 7 with focal segmental glomerulosclerosis (FSGS) and 16 healthy age-matched controls. Nine MCNS patients were in relapse and 14 in remission. Enzyme activity is expressed as micromoles per milligram urinary creatinine. In FSGS, NAG excretion correlated with the following: blood urea nitrogen (BUN) (r = 0.8), serum protein (r = 0.57), serum cholesterol (r = 0.85), serum albumin (r = -0.68) and proteinuria (r = 0.56). In FSGS the gamma-GT excretion was not significantly different from MCNS in remission or in relapse. In FSGS, gamma-GT excretion correlated with the following: BUN (r = 0.48), serum creatinine (r = -0.66), serum protein (r = -0.54), serum albumin (r = -0.68) and serum cholesterol (r = 0.87). Compared with controls, the urinary excretion of 5 amino acids was increased in FSGS patients as a possible indicator of tubular damage. The value for 7 amino acids was reduced in MCNS patients. Urinary amino acid excretion was not different from controls for the other amino acids in either FSGS or MCNS.(ABSTRACT TRUNCATED AT 250 WORDS)

Morbidity among municipal waste incinerator workers

Objective: The present study investigated the olfactory function in workers exposed to moderate airborne cadmium (Cd) levels, with the purpose of identifying possible early adverse effects of the metal, not demonstrable with the traditional diagnostic methods. Methods: The exposed group consisted of 33 men employed in cadmium fusion, sintering and alloys lamination. Two reference groups were considered: the first consisted of 39 subjects assigned to manual workings, but not exposed to harmful substances for olfaction (drivers, warehousemen); the second was characterized by 23 subjects exposed to iron and steel welding fumes (iron base alloys), non-specific irritants on the respiratory tract. Olfactory threshold and odor identification ability were separately quantified. Individual occupational exposure was studied by calculating the mean blood and urinary cadmium values (CdB and CdU, respectively) of the five years period during which, for each worker, the highest levels of dose indicators were measured. As indicator of renal tubular damage, urinary β2-microglobulin levels in the same quinquennium were monitored. Results: Mean olfactory threshold scored significantly higher in Cd workers (−5.26 log10 v/v, P=0.02) than did in controls (welders: −5.78 log10 v/v; P=0.26 compared to non-exposed −6.37 log10 v/v). The odor identification test findings for Cd workers were similar to those of the reference groups. Moderate blood and urine cadmium levels (mean CdB 3.7 μg/l; mean CdU 4.4 μg/g creatinine) accompanied threshold impairment. Olfactory threshold weakening was confirmed in the subgroup of Cd workers in which urinary β2-microglobulin never exceeded 300 μg/l (−5.41 log10 v/v; P=0.045 compared to non-exposed). Conclusions: These data suggested that possible early toxic effects of the metal can occur at low levels, close to the limits proposed by the American Conference of Governmental Industrial Hygienists (ACGIH®), confirming the hypothesis that primary olfactory neuron may represent the early target for cadmium toxic action. The action of the metal seemed to be due to an elective tropism for the olfactory epithelium and not to a non-specific irritant effect on the nasal cavity. The mechanism of this effect did not appear linearly dose-related. These findings underline the importance of olfactory tests to identify the early effects of xenobiotics even at low-exposure levels, and to contribute to verify the adequacy of the current exposure limits.

Alanine aminopeptidase and beta 2-microglobulin excretion in patients receiving vancomycin and gentamicin.

The effects of vancomycin, gentamicin, and combination vancomycin-gentamicin treatments on alanine aminopeptidase (AAP) and beta 2-microglobulin (beta 2M) elimination in 30 hospitalized patients were assessed and compared with elimination in a control group. Twenty-four-hour urine excretion values for AAP and beta 2M were determined on treatment day 1 and day 5 for patients receiving the three treatment regimens and for the control group. AAP excretion values for the vancomycin-treated group were not found to be statistically different from those of the control group. Both the gentamicin and the vancomycin-gentamicin groups had statistically higher AAP excretion values on treatment day 1 as well as on treatment day 5 when compared with the vancomycin and control groups. AAP excretion on day 5 of treatment was highest for the vancomycin-gentamicin group. Overall, beta 2M elimination was variable in all treatment groups. Although the beta 2M values were elevated as early as day 1 in all treatment groups, they were significantly elevated only in the vancomycin-gentamicin group on day 1 and only in the gentamicin group on day 5 compared with the vancomycin and the control groups. AAP appears to be a sensitive indicator of renal tubular damage. The combination of vancomycin and gentamicin results in greater AAP excretion than does either agent alone.

Reliability of urinary N-acetyl-beta-D-glucosaminidase as an indicator of renal tubular damage in neonates.

Urinary N-acetyl-beta-D-glucosaminidase (NAG) was determined in infants during the first year of life to clarify its evolutional change and the reliability of this enzyme as a marker of renal tubular damage in the newborn period. During the first 2 weeks of life, there was no difference in the urinary levels between preterm (gestational age of 33-36 weeks) and full-term infants. The urinary NAG index (NAG is expressed as the ratio of the enzyme activity to milligrams of creatinine) during the first month of life was significantly elevated when compared with that of any other succeeding period and gradually decreased during the first year of life. The index in newborn infants on tobramycin was significantly elevated and maintained a higher value during the 5 days after withdrawal of the medication. Infants with asphyxia had a higher urinary NAG index during the first week of life. These data suggest that the urinary NAG index is a useful indicator of renal tubular damage during the newborn period.

Elevation of Urinary Trehalase and Maltase Activities with Maturity-Onset Diabetes Mellitus

In the case of maturity-onset diabetes mellitus, urinary trehalase and urinary maltase activities were significantly elevated as compared with those of healthy individuals. The urinary trehalase activity in non glucosuric and non proteinuric patients was higher than that in healthy individuals, and the trehalase activity in those diabetics with proteinuria was significantly higher than in those without it (p<0.05). Both urinary trehalase and maltase activities were elevated with increased concentration of urinary β2-microglobulin in this diabetics. Furthermore, urinary trehalase was elevated in disease of short duration (1-4 years), whereas in that of relatively long duration (more than 13 years) the activity was rather low. These results suggest that renal brush borders are damaged in the early stages of the disease and that urinary trehalase is a good indicator of renal tubular damage.

Significance of elevated urinary N-acetyl- β-D-glucosaminidase activity in chronic cadmium poisoning

N-Acetyl- β-D-glucosaminidase (NAG) activity and β 2-microglobulin ( β 2-m) concentration were measured in the urine of inhabitants of a cadmium-polluted area (Cd), including patients with, or suspected, “itai-itai” disease and control subjects. Urinary NAG activity increased with increasing β 2-m concentration up to about 100 U/g creatinine; above this value the NAG activity did not increase with increasing β 2-m concentration. Urinary NAG activity thus represents another useful indicator of renal tubular damage caused by Cd poisoning since the mechanisms for the excretion of NAG and β 2-m into urine are thought to be different.

Stabilization of alanine aminopeptidase, gamma glutamyltranspeptidase, and N-acetyl-beta-D-glucosaminidase activity in normal urines.

The question of assessing renal toxicity in studies of humans exposed to environmental toxicants is of major concern in health effects studies. The measurement of urinary enzymes is a reliable, sensitive indicator of renal tubular damage due to a variety of causes, including heavy metal and drug toxicity. However, urine is not a favorable matrix for some enzymatic activities because certain enzymes are less stabile in urine than in a matrix such as serum. This study addresses the problem of the lack of stability of alanine aminopeptidase (AAP) and gamma glutamyltranspeptidase (GGT) in the urinary matrix. Four urinary treatment methods consisting of dialysis or the addition of albumin, dimethyl sulfoxide, or glycerol have been examined and compared. The activities of AAP, GGT, andN-acetyl-Β-D-glucosaminidase (NAGA) in six normal treated and untreated urines were followed for 28 days at 4‡C and for 6 months at −20‡C. This study indicates that of the methods tested, giycerol treatment provides the most stable AAP and GGT activity and is the most reliable method for stabilizing these enzymes in frozen urine. Even with giycerol treatment, some GGT activity is lost (mean loss of 11% over 6 months at −20‡C), indicating GGT should be assayed as soon as possible. NAGA activity is most stable in untreated urines but still increases by approximately 9% (mean of six samples) in 6 months at −20‡C. The implications of observed effects of dialyzable inhibitors are discussed for the three enzymes.

α 1-Microglobulin in urine as an indicator of renal tubular damage caused by environmental cadmium exposure

α 1-Microglobulin (α 1-m) was determined in the urine of both the cadmium-exposed and nonexposed subjects and was compared with those of other urinary parameters such as β 2-microglobulin (β 2-m), glucose, total protein or amino acids. Large amounts of α 1-m were detected in the urine of cadmiumexposed subjects. There were significant correlations between α 1-m and other urinary parameters. The sensitivity and specificity of both α 1-m and β 2-m as indices of tubular dysfunction caused by cadmium was similar. It was concluded that α 1-m in urine seemed to be a useful indicator of renal tubular dysfunction caused by cadmium.

Renal Allograft Rejection

Daily determinations of urinary lysozyme levels, serum β_1C(C3) and β_1E(C4)globulin concentrations, number of small mononucleated cells in the urinary sediment, and serum heterophil-antibody titers were carried out in 22 patients undergoing renal allotransplantation in order to determine which of these alterations are related to rejection episodes. Small mononuclear cells appeared in the urinary sediment at irregular intervals and displayed no relationship to onset of rejection. Similarly, heterophil-antibody titers rose in relation to only half the episodes of acute rejection, and similar fluctuations were observed in six of 11 patients who did not undergo acute rejection reactions. Urinary lysozyme excretion, on the other hand, was a sensitive indicator of renal tubular damage, and instability of serum complement levels occurred during clinically diagnosed rejection episodes.

Renal allograft rejection. An analysis of lysozymuria, serum complement, lymphocyturia, and heterophil antibodies.

Daily determinations of urinary lysozyme levels, serum β 1C (C3) and β 1E (C4)globulin concentrations, number of small mononucleated cells in the urinary sediment, and serum heterophil-antibody titers were carried out in 22 patients undergoing renal allotransplantation in order to determine which of these alterations are related to rejection episodes. Small mononuclear cells appeared in the urinary sediment at irregular intervals and displayed no relationship to onset of rejection. Similarly, heterophil-antibody titers rose in relation to only half the episodes of acute rejection, and similar fluctuations were observed in six of 11 patients who did not undergo acute rejection reactions. Urinary lysozyme excretion, on the other hand, was a sensitive indicator of renal tubular damage, and instability of serum complement levels occurred during clinically diagnosed rejection episodes.