The role of alpha1-antitrypsin in total hip replacement: a pilot study.

BACKGROUND: Lungs exposed to particulate debris may be damaged by proteolytic enzymes during phagocytosis. Damage is worse if patients are deficient in alpha1-antitrypsin (A1AT), which helps neutralise these enzymes. We investigated the possibility that A1AT deficiency contributes to aseptic loosening following total hip replacement (THR) when wear particles are phagocytosed. METHOD: A1AT level and phenotype were measured in patients attending for revision THR within 15 years of implantation. Periprosthetic lysis was graded from radiographs by three hip surgeons with an interest in revision, blinded to history and A1AT results. Patients were grouped according to presence of high or low levels of lysis radiologically. Mean A1AT levels were calculated for the two groups. RESULTS: 17 patients were recruited, mean age 69.5, mean interval between surgery and onset of pain 8.3 years (2-12). Two were heterozygotes for the less active S form of A1AT and therefore mildly deficient. Time to onset of pain in both was 12 years. Radiographs were available for 12 patients. Combining the results for all reviewers the probability of a difference in the level of A1AT between the high and low lysis groups reached statistical significance (p=0.008). For all reviewers, the mean A1AT level in their high lysis group was raised and greater than that of their low lysis group. Both A1AT-deficient patients were classified as high lysis by all reviewers. CONCLUSIONS: The incidence of A1AT deficiency is only marginally higher in this group than in the general population therefore A1AT deficiency is unlikely to be a common cause of failure of hip replacements. Elevated levels of A1AT in the presence of lysis suggest that A1AT may play a role in the aetiology of aseptic loosening. A1AT-deficient patients may be at increased risk of osteolysis. Further work is needed to evaluate this and to assess vulnerability of A1AT-deficient patients to lysis.

Effects of storage at -20 degrees C on ischaemia-modified albumin results.

BACKGROUND: Ischaemia-modified albumin (IMA) is being studied as a new marker for reversible ischaemia in patients presenting with possible cardiac chest pain. The conditions under which samples are stored prior to analysis may be critical in influencing the analytical result and hence the cut-off used in any particular study. METHODS: Sixty-eight samples taken during a study assessing the performance of IMA for risk stratification in patients presenting with possible cardiac chest pain were analysed both within 2.5 h of collection and after periods of storage at -20 degrees C. RESULTS: Samples stored at -20 degrees C yielded IMA values on average 3 units higher than those analysed within 2.5 h (mean 90.5 vs. 87.5; P < 0.00001). A Bland-Altman plot showed that the difference was not concentration dependent. CONCLUSIONS: These results indicate that decision cut-offs will be influenced by conditions of sample storage prior to IMA analysis, and that these should be stated in detail for each study.

The PRIMA study: presentation ischaemia-modified albumin in the emergency department.

OBJECTIVES: To investigate the diagnostic accuracy of presentation ischaemia-modified albumin (IMA), in addition to cardiac troponin I (TnI), as a strategy to rapidly ascribe low risk to patients with chest pain attending an emergency department, and to determine whether IMA has the potential to reduce transit time in emergency departments. METHODS: A prospective observational study was carried out in two emergency departments (belonging to the John Radcliffe Hospital, Oxford, UK; and the Frenchay Hospital, Bristol, UK) of similar size. Consecutive adult patients presenting with features of possible ischaemic cardiac chest pain and a normal electrocardiogram were eligible. The index test (measurement of IMA and TnI at presentation) and reference standard (delayed TnI measurement, taken at least 8 h after pain onset) were applied to all recruited patients. All clinicians were blinded to the results of the index test. Assays were carried out in a single laboratory using standard techniques. RESULTS: 399 patients were recruited; 277 patients had a result for both the index test and reference standard. The sensitivity was 97.6% (95% confidence interval (CI) 87.4 to 99.9), negative predictive value 97% (95% CI 84.2 to 99.9) and specificity 13.6% (95% CI 9.5 to 18.7). Sensitivity analysis showed similar findings in three alternative scenarios. Receiver operating characteristic analysis indicated that a different "cut-off" value for IMA would not improve the properties of the test. The median potential time saved (n = 268) was 6 h and 10 min. CONCLUSION: The diagnostic accuracy of presentation IMA in this study does not support its use as an effective risk stratification tool for patients with chest pain in the emergency department. The sensitivity is insufficiently high, with a small number of false negatives undermining the safety of the test. Frequent false positives produce a low specificity that limits the practical value of the test.

Is cerebrospinal fluid spectrophotometry useful in CT scan-negative suspected subarachnoid haemorrage?

Missed cerebral aneurysms in CT-negative patients can have serious implications. We set out to determine the usefulness of cerebrospinal fluid (CSF) spectrophotometry and the individual significance of CSF oxyhaemoglobin, bilirubin and methaemoglobin in 463 CT scan-negative patients with suspected subarachnoid haemorrhage (SAH) and normal neurological examination. CSF spectrophotometry resulted in the diagnosis of an intracranial aneurysm in 2% (9/463) of patients with CT-negative suspected SAH. No aneurysms were found in patients in whom spectrophotometry was negative for haem pigments. Less than 1% of patients with oxyhaemoglobin alone had aneurysms diagnosed, whilst 21% of patients with bilirubin had an aneurysm. CSF spectrophotometry is an important investigation in patients with CT-negative suspected SAH, particularly where clinical suspicion is strong. Patients positive for bilirubin are likely to provide a high yield of aneurysmal bleed and should undergo angiography. Patients with oxyhaemoglobin alone in whom SAH is strongly suspected may benefit from angiography. Based on a small number of patients, we recommend that patients with methaemoglobin should also be investigated. Patients with negative spectrophotometry are unlikely to benefit from further investigation.

Increased urinary albumin and retinol-binding protein in type I diabetes. A study of identical twins.

OBJECTIVE: Indexes of early renal glomerular and tubular dysfunction have been demonstrated in type I diabetes, but it remains uncertain whether such changes are genetically determined or are secondary to the disease process. We therefore undertook to study whether early markers of renal dysfunction are a consequence of type I diabetes or inherited. RESEARCH DESIGN AND METHODS: We estimated both urinary albumin excretion (UAE) and urinary retinol-binding protein (RBP) in 51 identical twin pairs discordant for type I diabetes and in 51 matched control subjects. RESULTS: UAE and RBP were significantly higher in the diabetic twins than in their nondiabetic co-twins (P < 0.0001 and P < 0.0002, respectively). Seven diabetic twins had elevated UAE, but none of the nondiabetic co-twins did. In a subgroup of 44 twins with normal UAE (albumin excretion rate < 20 micrograms/min), diabetic twins had both a higher albumin excretion function (median [range]; 0.64 [0.18-2.74] mg/mmol creatinine) than their nondiabetic co-twins (0.48 [0.24-1.40], P < 0.01) and higher levels of RBP excretion (10.4 [4.0-167.0] micrograms/mmol creatinine) than their nondiabetic co-twins (7.5 [0.97-23.0], P < 0.05). Values between twins of a pair were significantly correlated for RBP (r = 0.36, P < 0.05) but not for UAE (r = 0.13). CONCLUSIONS: These results suggest that in type I diabetes, an index of renal tubular function (RBP), but not glomerular function (UAE), is influenced by shared genetic and nongenetic factors. Type I diabetes can affect renal tubular function even when glomerular function is normal. We conclude that neither the increased UAE nor urinary RBP found in type I diabetes is inherited independently of the diabetes process.

A radioimmunoassay for human urinary prealbumin.

We describe a validated radioimmunoassay for prealbumin in urine. Using timed overnight urine samples, the normal reference range was less than 10-148 micrograms/L; or less than 1.8-9.6 micrograms/mmol creatinine, excretion in women being significantly greater than in men (P < 0.05); or less than 7.3-114 ng/min with no significant difference in excretion rate between the sexes. Urines exhibited loss of immunoreactivity after storage at -20 degrees C and thawing. No such loss occurred after storage for 4 weeks at 4 degrees C or room temperature. The urinary excretion of prealbumin was highly correlated with that of albumin (r = 0.85), and clearance relative to creatinine was 2 x 10(-6), the same order as that of albumin.

The assessment of subclinical ifosfamide-induced renal tubular toxicity using urinary excretion of retinol-binding protein.

The excretion of retinol-binding protein in early morning urine samples, expressed as a ratio to urinary creatinine (RBPCR), was used as a measure of proximal renal tubular toxicity in children during or after treatment with ifosfamide-containing chemotherapy. The results showed a progressive increase in renal tubular leak after exposure to ifosfamide that persisted after treatment. The toxic effect appeared to be greatest in younger children and at least partly dose-dependent, although partially reversible after each course of chemotherapy. However, few patients had related symptoms and none experienced major metabolic difficulty. RBPCR appears to offer a sensitive and noninvasive way of monitoring sequential change in renal tubular function after exposure to ifosfamide. Further studies are required to define more clearly the effect of cumulative dose, age, and drug scheduling and to identify whether a level of renal tubular dysfunction, measured by RBPCR or a similar noninvasive technique, can identify a threshold beyond which further exposure to ifosfamide is likely to be significantly and permanently damaging.

Urinary albumin and low molecular weight protein excretion in the nephrotic syndrome--sequential studies during corticosteroid treatment.

In a preliminary investigation into the behaviour of low molecular weight proteins in the nephrotic syndrome, we have measured urinary concentrations of albumin, alpha-1-microglobulin (alpha 1-m) and retinol-binding protein (RBP) in six children for up to 11 days during the course of steroid therapy for nephrotic syndrome. The results in part support the concept of independent proximal tubular absorption of albumin and low molecular weight proteins, and indicate that in the nephrotic syndrome the excretion of RBP and alpha 1-m, two generally accepted markers of tubular proteinuria, is anomalous.

Influence of energy and nitrogen contents of enteral diets on nitrogen balance: a double blind prospective controlled clinical trial.

Results of recent controlled studies show that because of difficulties in administering adequate quantities of enteral diet, positive nitrogen balance is not consistently achieved during enteral feeding. In order to determine whether nitrogen balance can be improved in routine clinical practice by prescribing enteral diets containing higher concentrations of nutrients, 118 patients with normal gastrointestinal function needing enteral nutrition were randomised to receive daily 21 of one of three polymeric diets: Standard diet (1.0 kcal/ml; 6.3 gN/l), Energy Dense diet (1.5 kcal/ml; 7.8 gN/l), and Energy-Nitrogen Dense diet (1.5 kcal/ml; 9.4 gN/l. The three diets, administered by continuous nasogastric infusion, were equally well tolerated. Results were analysed only for patients fed five or more days and who received at least 60% of prescribed enteral diet (n = 42). Positive nitrogen balance was achieved only in the patients receiving the Energy-Nitrogen Dense diet (n = 16; + 1.6 (SE) 0.6 gN/d, compared with the Standard diet (n = 12; -3.8 (1.1) gN/d; p less than 0.001), and the Energy Dense diet (m = 14; -1.9 (0.8) gN/d; p less than 0.005). As the findings of this prospective controlled trial show that positive nitrogen balance was not consistently achieved by administering 21 enteral diet containing up to 15.6 gN, consideration could, therefore, be given to routinely using enteral diets containing up to 9.4 gN/l.

Urinary excretion of albumin and retinol-binding protein during normal pregnancy.

In a cross sectional study of 88 pregnant women urinary excretion of albumin, when expressed as a ratio to creatinine concentration, was not significantly different from that in a non-pregnant control group of similar age (p greater than 0.05) and did not change significantly during pregnancy. Only when albumin excretion was expressed as a fractional clearance was the urinary excretion significantly increased in the third trimester compared with the first trimester (p less than 0.05), although it was still not significantly different from that in the non-pregnant control group. Excretion of retinol-binding protein was significantly increased during all three trimesters of pregnancy (p less than 0.01 in each case) and more so in the second and third trimesters than in the first. It is concluded that the increased total protein excretion that has been described during pregnancy is not explained by an increased excretion of albumin which remains essentially normal. In contrast, the tubular absorption of proteins is decreased.

Urine concentrations of apolipoprotein AI in renal tubular proteinuria.

To test the hypothesis that a significant proportion of apolipoprotein AI (apoAI) metabolism occurs through glomerular filtration of free apoAI in serum and subsequent renal tubular metabolism, we have examined the urine concentration of apoAI in three situations in which proximal tubular reabsorption of another protein metabolized in this manner and retinol-binding protein (RBP) was impaired. Following infusion of a cross-linked gelatin polymer (Haemaccel) in four normal subjects, urine RBP excretion (normally about 100 micrograms/L), was between 14 and 46 mg/L, while urine apoAI excretion was less than 0.5 mg/L. On the third day following cardiac surgery involving Haemaccel infusion, urine RBP was between 27 and 159 mg/L while urine apoAI excretion was again less than 0.5 mg/L. In 16 samples from eight patients recently transplanted with allograft kidneys, urine RBP was between 9 and 70 mg/L, whereas in only two samples was apoAI detected in the urine at 0.5 mg/L. These results have been taken to indicate that significant metabolism of apoAI through glomerular filtration and tubular absorption is unlikely to occur in humans.