The Royal College of Pathologists' CME scheme.
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Curriculum↗
Biomedical subjects
F V Flynn
Publications and source records attributed to F V Flynn.
Beta 2-glycoprotein-1 (apolipoprotein H) excretion and renal tubular malfunction in diabetic patients without clinical proteinuria.
AIM: To compare the urinary excretion of beta 2-glycoprotein-1 with that of two other markers of early tubular disorder in diabetic patients without clinical proteinuria. METHODS: The urinary excretion of retinol binding protein, beta 2-glycoprotein-1, and N-acetyl-beta-D-glucosaminidase was measured in 90 known diabetic patients who had a negative reagent strip test for proteinuria. RESULTS: Among 43 patients with urinary albumin excretion within the reference range, 23 (53%) had raised urinary N-acetyl-beta-D-glucosaminidase activity, five (12%) increased excretion of beta 2-glycoprotein-1, and five (12%) increased loss of retinol binding protein. Among 47 patients with an albumin excretion of 0.9-7.9 mg/mmol creatinine, 42 (89%) had increased urinary N-acetyl-beta-D-glucosaminidase, 23 (49%) an increased output of beta 2-glycoprotein-1, and 16 (34%) a raised excretion of retinol binding protein. The excretion of these markers of tubular defects seldom exceeded two and a half times the upper reference limit and the differences between the findings in the insulin dependent and non-insulin dependent patients with similar albumin excretion were small and insignificant. CONCLUSIONS: In diabetic patients with a negative dipstick test for proteinuria: (a) assay of urinary beta 2-glycoprotein-1 may be a more sensitive test for the detection of impaired tubular reabsorption of protein than measurement of retinol-binding protein; (b) assay of N-acetyl-beta-D-glucosaminidase can detect tubular injury at a time when protein reabsorption remains normal; and (c) impaired renal tubular function may be present in the absence of evidence of glomerular malfunction.
Acetylglucosaminidase↗
Urinary excretion of beta 2-glycoprotein-1 (apolipoprotein H) and other markers of tubular malfunction in "non-tubular" renal disease.
AIM: To determine whether urinary beta 2-glycoprotein-1 assays can provide improved discrimination between chronic renal diseases which are primarily of tubular or glomerular origin. METHODS: Urinary beta 2-glycoprotein-1, retinol-binding protein, alpha 1-microglobulin, beta 2-microglobulin, N-acetyl-beta-D-glucosa-minidase and albumin were measured in 51 patients with primary glomerular disease, 23 with obstructive nephropathy, and 15 with polycystic kidney disease, and expressed per mmol of creatinine. Plasma beta 2-glycoprotein-1 was assayed in 52 patients and plasma creatinine in all 89. The findings were compared between the diagnostic groups and with previously published data relating to primary tubular disorders. RESULTS: All 31 patients with plasma creatinine greater than 200 mumol/l excreted increased amounts of beta 2-glycoprotein-1, retinol-binding protein, and alpha 1-microglobulin, and 29 had increased N-acetyl-beta-D-glucosaminidase; the quantities were generally similar to those found in comparable patients with primary tubular pathology. Among 58 with plasma creatinine concentrations under 200 mumol/l, increases in beta 2-glycoprotein-1, retinol-binding protein, and alpha 1-microglobulin excretion were less common and much smaller, especially in those with obstructive nephropathy and polycystic disease. The ratios of the excretion of albumin to the other proteins provided the clearest discrimination between the patients with glomerular or tubular malfunction, but an area of overlap was present which embraced those with obstructive nephropathy and polycystic disease. CONCLUSIONS: Increased excretion of beta 2-glycoprotein-1 due to a raised plasma concentration or diminution of tubular reabsorption, or both, is common in all the forms of renal disease investigated, and both plasma creatinine and urinary albumin must be taken into account when interpreting results. Ratios of urinary albumin: beta 2-glycoprotein-1 greater than 1000 are highly suggestive of primary glomerular disease and those less than 40 of primary tubular disease. Used in this way, beta 2-glycoprotein-1 assays provide superior discrimination between glomerular and tubular malfunction when compared with retinol binding protein but the best discrimination is provided by albumin: alpha 1-microglobulin ratios.
Acetylglucosaminidase↗
Absence of increased urinary excretion of adenosine-deaminase-binding protein by patients with chronic renal tubular malfunction.
The urinary excretion of adenosine-deaminase-binding protein, a constituent of the brush border of proximal renal tubule cells, has been investigated in 39 patients with disorders associated with malfunction of the renal tubules, and its excretion has been compared with that of two low molecular mass plasma proteins and an enzyme derived from renal tubular cells. None of the 36 patients with disorders associated with chronic renal tubular malfunction were found to be excreting significantly increased quantities of adenosine-deaminase-binding protein but 30 had increased excretion of retinol-binding protein, alpha 1-microglobulin, or N-acetyl-beta-D-glucosaminidase. Measurement of urinary adenosine-deaminase-binding protein may be useful in the assessment of acute renal tubular injuries but it is not of value in the detection of chronic renal tubular disorders.
Acetylglucosaminidase↗
Beta 2-glycoprotein-1 (apolipoprotein H) excretion in chronic renal tubular disorders: comparison with other protein markers of tubular malfunction.
Urinary beta 2-glycoprotein-1 was measured in 60 patients with conditions recognised as causing renal tubular impairment and compared with established markers of early tubular malfunction. Increased beta 2-glycoprotein-1 excretion was found in 49 (82%) of the subjects; raised excretion of alpha 1-microglobulin, retinol-binding protein, and beta 2-microglobulin was found in 46 (77%), 45 (75%), and 31 (52%), respectively, and increased urinary N-acetyl-beta-D-glucosaminidase activity in 32 of 54 of the subjects (59%). The increase was particularly pronounced in those with proximal tubule malfunction, although considerable variation occurred. beta 2-glycoprotein-1 was shown to be stable in urine over the physiological pH range, and it is concluded that its measurement provides a means of detecting chronic malfunction of the renal tubules that is marginally more sensitive than assays of alpha 1-microglobulin or retinol-binding protein, and more reliable than assays of beta 2-microglobulin or N-acetyl-beta-D-glucosaminidase.
Acetylglucosaminidase↗
Screening for presymptomatic disease.
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Humans↗
A sandwich enzyme-linked immunosorbent assay for beta 2-glycoprotein I.
A solid-phase sandwich enzyme-linked immunosorbent assay for determining beta 2-glycoprotein I in urine has been developed. It has a working concentration range of 5-40 micrograms/L and a detection limit of approximately 1.4 micrograms/L. The within-plate coefficient of variation (CV) falls between 1.4% and 2.1%, and the between-batch CV ranges from 5.2 to 6.0%. Recovery of beta 2-glycoprotein I added to urine varies between 96 and 110%. The assay can also be used for determining beta 2-glycoprotein I in serum.
Adult↗
Excretion of beta 2-glycoprotein I (apolipoprotein H) in renal tubular disease.
beta 2-Glycoprotein I (beta 2GI) was identified as a major urinary protein excreted by patients with several renal tubular diseases, including adult Fanconi syndrome, nephrocalcinosis associated with autoimmune diseases, Lowe's syndrome, and Dent's disease (a familial renal tubular disease). Sixteen patients excreted between 2 and 40 mg of beta 2GI per millimole of creatinine. In contrast, 18 healthy controls had undetectable amounts of beta 2GI in urine. Isoelectric focusing followed by immunoblotting demonstrated multiple forms of beta 2GI with pls between 6.4 and 8.2. These pls are higher than for several other "tubular proteins"; beta 2GI may therefore be less retarded than more-anionic proteins by the glomerular charge-barrier. This could explain why large quantities of beta 2GI are excreted despite its relatively high molecular mass (50 kDa). Excretion of beta 2GI was easily demonstrated by routine electrophoresis of urine proteins. beta 2GI migrates in the beta-gamma region and may be confused with Bence Jones protein. beta 2GI is stable for at least two years in urine frozen at -25 degrees C.
Adolescent↗
Assessment of renal function: selected developments.
Tests commonly used to assess the glomerular filtration rate (GFR) and to detect renal tubular damage are critically reviewed. Creatinine clearance which is frequently used for assessment of the GFR is prone to several errors. The plasma creatinine can be used to provide a rough guide but for reliable measurement of the GFR, 51Cr-EDTA clearance is recommended. Measurements of the urinary excretion of low molecular weight proteins, enzymes and kidney tissue proteins have been used to detect tubular damage. Of the low molecular weight proteins excreted, beta-2-microglobulin is unstable and measurement of retinol-binding protein or alpha-1-microglobulin is recommended for the detection of chronic renal tubular malfunction. Of the many enzymes that have been studied, urinary N-acetyl-beta-D-glucosaminidase or alanine aminopeptidase are recommended as being the most useful for the early detection of acute renal tubular damage. Among renal tissue proteins that have been measured in urine adenosine-deaminase-binding protein, a tubular brush border antigen appears to have considerable potential for providing early warning of renal allograft rejection.
Glomerular Filtration Rate↗
Renal impairment in myeloma: negative association with isoelectric point of excreted Bence-Jones protein.
The isoelectric point (pI) of the major form of Bence-Jones protein excreted by 62 patients with myeloma and six with macroglobulinaemia was measured by combining isoelectric focusing with immunoblotting techniques. The distribution of the pI values for both kappa and lambda type proteins was bimodal, most falling in the ranges 5.0-6.0 and 7.0-7.5. Plasma creatinine and creatinine clearance and the urine excretion of alpha-1-microglobulin and beta-2-microglobulin were measured in 24 of the patients. These patients, who were free of additional factors known to have an association with the development of renal impairment, were followed up for a mean period of 16 months (range three to 28 months). It was found that renal impairment was not related to the pI of the Bence-Jones protein excreted.
Alpha-Globulins↗
What every doctor needs to know about 11 November.
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Confidentiality↗
Immunoglobulin light-chain immunoblots of urine proteins from patients with tubular and Bence-Jones proteinuria.
Immunoglobulin excretion by patients with monoclonal gammopathies and tubular proteinuria has been analysed by agarose gel isoelectricfocussing of untreated urine and immunoblotting. About three-quarters of the Bence-Jones proteins detected occurred as multiple bands on isoelectricfocussing; in about half of these cases the multiple forms were due to polymerisation or fragmentation of the light chains. In specimens with tubular proteinuria, a characteristic light chain pattern of three broad bands covering the pI ranges 7.1-7.3, 7.8-8.0 and 8.3-8.5 was found. This pattern also occurred in 53% of specimens with Bence-Jones proteinuria and was identical to that found in concentrated normal urine. Intact monoclonal immunoglobulin usually appeared as three or more evenly spaced bands of similar intensity whereas polyclonal intact immunoglobulins produced diffuse staining from pI 5.0-8.5. A scheme for the qualitative analysis of urinary immunoglobulin excretion using this technique has been developed.
Adult↗
Bence Jones protein detection: a rapid immunoblotting technique for routine use on unconcentrated urine.
A new immunoblotting method is described for the detection of Bence Jones proteinuria by the routine laboratory. Unconcentrated urine specimens are subjected to electrophoresis on agarose gels. Separated proteins are transferred to a nitrocellulose membrane and the immunoglobulins located and identified by horseradish-peroxidase double-antibody staining. The new method has been compared with that used routinely, and an improved rate of detection of both Bence Jones protein and intact urinary monoclonal immunoglobulin has been obtained. Among urine specimens received for routine testing for Bence Jones protein from 83 patients, 64 monoclonal components were found by the new technique compared with 45 by the method used routinely. Other advantages of the new procedure include: no need to concentrate urine specimens before electrophoresis; unlike immunofixation, the proteins may be detected successfully over a wide concentration range without using several specimen or antibody dilutions; and interpretation is easier.
Bence Jones Protein↗
Detection of Bence-Jones protein by isoelectric focussing of unconcentrated urine followed by nitrocellulose blotting and immunoperoxidase staining.
Urine specimens from 164 patients sent to the laboratory for testing for Bence-Jones proteinuria were investigated using a new procedure. The protein in the untreated urine was subjected to isoelectric focussing in an agarose gel, transferred to a nitrocellulose membrane by blotting, and then stained by an immunoperoxidase technique for either immunoglobulin kappa or lambda chains. This technique was compared with a routine procedure for the detection of immunoglobulin light chains involving concentration by ultrafiltration, electrophoresis and then immunofixation. The new technique achieved a much increased rate of detection of Bence-Jones proteinuria. Among 51 patients known to have myeloma or macroglobulinaemia, Bence-Jones proteinuria was detected in 35 cases with the new procedure and in only 27 by the conventional method. In 28 patients with paraproteinaemia without other evidence of myeloma, macroglobulinaemia, leukaemia or lymphoma, 12 instances of Bence-Jones proteinuria were discovered with the new procedure, 10 of which were missed by the conventional method. The improved efficiency of detection is attributed to the high resolution of isoelectric focussing and the avoidance of protein loss from adsorption on to ultrafiltration membranes.
Bence Jones Protein↗
Malaria chemoprophylaxis with chloroquine in young Nigerian children. IV. Its effect on haematological measurements.
Haematological measurements were made in 198 Nigerian children aged three months to two years who received weekly malaria chemoprophylaxis with chloroquine from shortly after birth until the age of one or two years and in 185 age-matched control children. Children protected against malaria had a higher mean haemoglobin level and a higher packed cell volume than control children, and they showed fewer abnormalities of their red cells. Total and differential white blood cell counts, mean plasma folate and mean serum ferritin concentrations were similar in both groups of children. However, the geometric mean red cell folate level of children exposed to malaria was significantly higher than the mean level of control children; and it may be that malaria raises the red cell folate through intracellular synthesis by malaria parasites. Children with malaria parasitaemia had a significantly lower haemoglobin and packed cell volume and a significantly higher geometric mean red cell folate and ferritin level than children without parasitaemia. Serum ferritin is probably an unreliable index of iron status in children with malaria.
Child, Preschool↗
Screening for steatorrhoea with an oxalate loading test.
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Adolescent↗
Degradation of beta 2-microglobulin in infected urine by leukocyte elastase-like activity.
Loss of beta 2-microglobulin in human urine at near neutral pH is described. beta 2-Microglobulin was found to be unstable at pH 7.4 in 15 out of 70 specimens with bacterial infection. Breakdown of this protein was shown to be most active between pH 6.5 and 8.0 but some proteolysis also occurred between pH 5.0 and 6.0. Evidence that proteolysis of beta 2-microglobulin near neutral pH is due to neutrophil elastase-like activity was obtained by the following methods: use of the model elastase substrate L-pyroglutamyl-L-prolyl-L-valine-p-nitroanilide and the specific inhibitor 2-trifluoroacetylaminobenzenesulphonyl fluoride; use of neutrophil granule extracts and determination of the size distribution of beta 2-microglobulin proteolytic fragments. If increased numbers of pus cells are present, it is suggested that screening for elastase-like proteolysis should be undertaken before interpreting a measurement of beta 2-microglobulin.
Acidosis, Renal Tubular↗
Iatrogenic hyponatraemia of the newborn due to maternal fluid overload: a prospective study.
Over five weeks 136 out of 246 deliveries were studied. Maternal plasma sodium concentrations were normal at admission. At delivery no significant difference was found between maternal and infant cord plasma sodium concentrations. Twenty-four of the 41 mothers who had received only oral fluids during labour had infants whose cord plasma sodium concentrations were normal. Of the 95 mothers who had been given intravenous fluids, however, only 14 infants with normal plasma sodium concentrations, 31 had a concentrations of 130 mmol (mEq)/1 or less and nine of these had a concentration of 125 mmol/1 or less. There was a highly significant inverse relation between cord plasma sodium concentration and rate of fluid administration, suggesting that hyponatraemia was due to intravenous treatment with predominantly sodium-free solutions. Endogenous antidiuretic activity probably increases during labour, and synthetic oxytocin in large doses has been shown to have an antidiuretic effect. The dose used in this study did not appear to have such an effect. Glucose solutions are often used as a vehicle for oxytocin; 83% of all fluid intake in this study was 5% or 10% glucose in water. Fluid balance in labour should be supervised closely, and oxytocin should be given in a more concentrated solution.
Birth Weight↗