Excretion Of Alpha 1-microglobulin Research Articles

P31 - A1M, an extravascular tissue cleaning and housekeeping protein: a possible drug candidate

Alpha-1-microglobulin (A1M) is a small protein found intra- and extracellularly in all tissues of vertebrates. The protein was discovered 40 years ago and its physiological role remained unknown for a long time. A series of recent publications have demonstrated that A1M is a vital part of tissue housekeeping. A strongly electronegative free thiol group forms the structural basis of heme-binding, reductase- and radical-trapping properties. A rapid flow of liver-produced A1M through blood and extravascular compartments ensures clearing of biological fluids from heme and free radicals and repair of oxidative lesions. After binding, both the radicals and A1M are electroneutral and therefore do not present any further oxidative stress to tissues. The biological cleaning cycle is completed by glomerular filtration, renal degradation and urinary excretion of A1M heavily modified by covalently linked radicals and heme-groups. Based on its role as a tissue housekeeping cleaning factor, A1M constitutes a potential therapeutic drug candidate in treatment or prophylaxis of diseases or conditions that are associated with pathological oxidative stress elements.

Proteinuria Is Reduced by Inhibition of Inducible Nitric Oxide Synthase in Rat Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion (IR)-induced nephrotoxicity is associated with proteinuria. There are reports on the involvement of inducible nitric oxide synthase (iNOS) in proteinuria in conjunction with renal disease. This study was designed to investigate the effect of N6-(1-iminoethyl)-L-lysine hydrochloride (L-Nil), a selective inhibitor of iNOS, to prevent proteinuria in IR injury. Ischemia was induced by 40-minute clamping of the renal arteries followed by 6-hour reperfusion. Rats were administered either L-Nil (3 mg/kg intravenous bolus followed by infusion of 1 mg/kg/h) or saline. To monitor glomerular and tubular functional changes before and after treatment, we measured blood urea nitrogen, plasma creatinine, and urinary N-acetyl-beta-D-glucosaminidase activity. Total protein (TP), albumin, and low- (LMW) and high-molecular-weight (HMW) protein excretion rates were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis of urine samples. Kidney ultrastructure was examined through a transmission electron microscope (TEM). IR resulted in significant LMW and HMW proteinuria. L-Nil significantly prevented the IR-induced increases in TP, albumin, and alpha1-microglobulin excretion. TEM showed loss of microvilli of the proximal tubule cells, injured mitochondria, and foamy changes in the structure of nuclear and cytoplasm in IR group. L-Nil reduced IR-mediated renal ultrastructural changes and tubular proteinuria. This study suggested possible differences in the mechanism(s) of nephrotoxicity induced by iNOS in the glomeruli and tubular cells. The types of proteins excreted in the urine should be considered in the treatment strategy. In conclusion, this study suggested the involvement of iNOS in IR-induced tubular proteinuria.

Urinary proteins in children with urinary tract infection

The aim of this study was to test our hypothesis that the urinary excretion of C-reactive protein (CRP), alpha 1-microglobulin (A1M), retinol-binding protein (RBP) and Clara cell protein (CC16) is increased in children with urinary tract infection (UTI) and relates to renal damage as measured by acute dimercaptosuccinic acid (DMSA) scintigraphy. Fifty-two children <2 years of age with UTI were enrolled in the study, 44 of whom were febrile. The control group consisted of 23 patients with non-UTI infection and elevated serum CRP (s-CRP) levels. Thirty-six patients had abnormal DMSA uptake, classified as mild, moderate or severe damage (DMSA class 1, 2, 3, respectively). There was a significant association between DMSA class and the excretion of urinary RBP (u-RBP) and u-CC16. There was also a significant difference in u-CRP levels between children with UTI and control children with non-UTI infections, although u-CRP excretion was not significantly correlated to DMSA class. In conclusion, the urinary excretion of the low-molecular-weight proteins RBP and CC16 showed a strong association with uptake defects on renal DMSA scans. The urinary level of CRP seems to distinguish between children with UTI and other febrile conditions. A combination of these biomarkers may be useful in the clinical assessment of children with UTI.

In Crescentic IgA Nephropathy, Fractional Excretion of IgG in Combination with Nephron Loss Is the Best Predictor of Progression and Responsiveness to Immunosuppression

The aim of this study was to evaluate the relationship between proteinuric markers (urinary excretion of IgG, alpha2-macroglobulin, alpha1-microglobulin) and serum creatinine (sCr), histologic lesions, progression, and immunosuppression responsiveness in crescentic IgA nephropathy. Fractional excretion of IgG (FEIgG) and of alpha1-microglobulin and urinary excretion of alpha2-macroglobulin were evaluated in 37 patients, 23 treated with steroids and cyclophosphamide. For assessment of the effective tubular load of proteins in surviving nephrons, new markers that take into account not only the absolute excretion value but also nephron loss were obtained dividing proteinuric markers for percentage of nonobsolescent glomeruli (surviving glomeruli [SG]). For each parameter, low- and high-risk groups were defined according to cutoffs with the highest sensitivity and specificity for progression (ESRD/doubling sCr) assessed by receiver operating characteristic analysis; follow up was 60 +/- 40 mo. FEIgG/SG is the most powerful progression predictor: 5 versus 83% in all patients; in treated patients, 0 versus 89%, increased to 0 versus 100% by sCr and FEIgG/SG in combination (low risk: both markers or only one below cutoff (n = 15); high risk: both markers above cutoff (n = 8). The nonprogressors showed at last observation 65% proteinuria reduction and 10% sCr reduction. In crescentic IgA nephropathy, FEIgG/SG, which evaluates altered size selectivity in relation to nephron loss, is the best progression predictor. In treated patients, progression prediction was increased by FEIgG/SG and sCr in combination. Treatment may be restricted to low-risk patients.

Dose-Dependent Effect of Rosuvastatin Treatment on Urinary Protein Excretion

Concerns have been raised because of observations of proteinuria associated with rosuvastatin treatment. In this open-label study, a potential dose-dependent effect was investigated of rosuvastatin on urinary protein excretion and renal function parameters in 90 hyperlipidemic patients randomly assigned to rosuvastatin 10 mg/day (n = 45) or 20 mg/day (n = 45). Urinary samples were collected from patients and 40 age- and gender-matched controls to determine electrolyte, uric acid, creatinine, and protein (total, albumin, IgG, and alpha1-microglobulin) levels at baseline and after 12 weeks. A dose-dependent increase in the excretion of alpha1-microglobulin (17.6% in rosuvastatin 10 vs 34.9% in rosuvastatin, 20 mg/day; P = .03 for the comparison between groups) was observed. A trend toward an increase in the estimated glomerular filtration rate was noted in only patients receiving 20 mg/day of rosuvastatin. These findings indicate that rosuvastatin treatment increases the urinary excretion of alpha1-microglobulin urinary excretion in a dose-dependent manner without adversely affecting renal function.

α-1 Microglobulin as a New Inflammatory Marker in Newly Diagnosed Hypertensive Patients

The alpha-1 microglobulin (A1M) is considered to be a marker of renal insufficiency, suggesting disturbed tubular function. In the present study we examined the ability of urinary A1M excretion to reflect the overall inflammatory status in patients with newly diagnosed essential hypertension and normal renal function. The study population consisted of 1445 nondiabetic patients with newly diagnosed arterial hypertension and no evidence of renal insufficiency. Serum levels of C-reactive protein (CRP), serum amyloid alpha (SAA), and plasma fibrinogen, as well as urinary A1M excretion, were estimated. Multivariate analysis was performed to evaluate the associations between hypertension; A1M urinary excretion; and circulating levels of CRP, SAA, and fibrinogen. Patients with systolic hypertension had higher CRP, SAA, fibrinogen, and A1M compared with patients with isolated diastolic hypertension (P < .0001 for all). In multivariate analysis, systolic (but not diastolic) blood pressure (BP) was independently associated with A1M, CRP, and SAA (P < .0001 for all), whereas urinary A1M was also independently correlated with inflammatory markers such as CRP (P = .0001) and SAA (P = .0001). Urinary A1M is independently associated with circulating acute phase proteins in patients with newly diagnosed hypertension, whereas it is closely associated with systolic but not diastolic BP. Our findings suggest that urinary alpha-1 microglobulin may reflect the overall inflammatory status in patients with newly diagnosed essential hypertension, beyond its value as a marker of renal function.

The influence of urinary flow rate in children on excretion of markers used for assessment of renal damage: albumin, γ-glutamyl transpeptidase, N-acetyl-β-D-glucosaminidase, and alpha1-microglobulin

The aim of the present study was to examine the influence of urinary flow rate on markers of renal function in children. A sub-study of the New England Children's Amalgam Trial collected 82 pairs of urine samples from children aged 10-16 years: a timed overnight collection and a spot daytime sample collected the following day. These samples were analyzed for albumin, gamma-glutamyl transpeptidase (gamma-GT), N-acetyl-beta-D-glucosaminidase (NAG), alpha1-microglobulin (A1M), and creatinine concentration. Regression analysis was used to model the effect of urinary flow rate in the timed overnight samples. A paired t-test compared concentrations and creatinine-corrected renal markers between overnight and daytime samples. Albumin, gamma-GT, NAG, and A1M excretion rates increased significantly with urinary flow rate. Their corresponding creatinine-corrected markers did not vary significantly with urinary flow rate, but the creatinine-corrected excretions of albumin, gamma-GT, and NAG were significantly higher in daytime samples than in overnight samples, with the same (non-significant) trend for A1M. The influence of urinary flow rate on creatinine-corrected markers of renal function was markedly less than its influence on excretion rates. Therefore, the use of creatinine-corrected markers seems to be a good choice in practice, with the caveat that daytime and overnight samples are not comparable.

Methodological issues on the use of urinary alpha-1-microglobuline in epidemiological studies

Alpha-1-microglobulin (A1M) is a low molecular weight protein that can be measured in urine and used as a marker for tubular function, assuming that the normal variability within and between individuals is known. The aims of this study were to investigate this variability, to find the optimal way of sampling and quantifying A1M in spot urine samples to reflect the 24 h excretion and to examine storage stability. Method. Timed urine specimens were collected from 29 healthy volunteers at fixed time points over 24 h on two separate days. Volumes, creatinine and specific gravity were determined. All samples were analysed with a commercial ELISA for A1M. We found a clear diurnal variation in A1M excretion rate and a gender effect (higher in males). The excretion rate was higher in the daytime, with high urinary flow, compared to overnight values. A1M excretion in spot urine samples was highly correlated with the 24 h excretion at all times except 22:00 in male subjects. Urinary A1M adjusted for creatinine concentration correlated well with the 24 h excretion. Variability within individuals was only 20% of the total variability in 24 h A1M excretion, but 43% in first morning urine. Expressed as CV, the intra-individual variability (between days) was 29% in 24 h excretion. We conclude that diurnal variation and gender should be taken into account when comparing groups. Moreover, in spot samples (e.g. first morning samples) adjustment of A1M for creatinine or specific gravity is a reliable alternative to 24 h urine.

Rosuvastatin Increases α‐1 Microglobulin Urinary Excretion in Patients With Primary Dyslipidemia

The renoprotective effect of statins has been recently disputed because of observations of proteinuria associated with rosuvastatin treatment, the newest drug of the class. Statin-induced proteinuria findings were mainly based on crudely quantitative dipstick assays. The authors quantitatively evaluated the effect of rosuvastatin at the recommended starting dose of 10 mg/d, on urine protein excretion in patients with primary dyslipidemia. Serum lipid and nonlipid parameters as well as urinary electrolyte, creatinine, and protein (total, albumin, immunoglobulin G, and alpha-1 microglobulin) levels were measured in 40 patients treated with rosuvastatin and 30 controls at baseline and after 12 weeks. The protein-to-creatinine ratios were used to assess urinary protein excretion. Rosuvastatin improved the lipid profile, produced no deterioration of kidney function, but induced a small but significant increase in the excretion of alpha-1 microglobulin (by 16%, P < .05) indicating that statin-related proteinuria involves low-molecular-weight proteins and is of proximal tubular origin.

Urinary excretion of alpha1-microglobulin and albumin in acute myocardial infarction

Microalbuminuria associated with myocardial infarction (MI) is normally ascribed to glomerular factors, but could just as well involve pathophysiological processes located in other parts of the nephron, e.g. proximal tubules where plasma albumin normally filtered through the glomerulus is almost completely reabsorbed. The aims of this study were to establish whether impaired tubular reabsorption of filtered albumin contributes to microalbuminuria during MI, and whether the urinary excretion of protein relates to plasma levels of C-reactive protein (CRP) and troponin I. We monitored plasma CRP and troponin I as well as the urinary excretion of albumin and alpha1-microglobulin, a low-molecular-weight plasma protein and marker of tubular proteinuria, in 18 patients with MI. The urinary excretion of alpha1-microglobulin and albumin was significantly elevated in nine patients, and the urinary excretion of the two proteins correlated significantly. A decrease in tubular reabsorption of albumin may thus be at least one of the causative factors underlying microalbuminuria during MI. The plasma levels of CRP and troponin I were also significantly higher in this group of nine patients, and correlated with urinary protein excretion, suggesting an interrelationship between inflammatory response and tubular dysfunction. Extrarenal inflammatory processes seem to affect renal tubular function, thereby contributing to microalbuminuria during MI.

Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass

The aim was to determine whether the administration of aprotinin can cause deleterious effects on renal function in cardiac surgery with cardiopulmonary bypass (CPB). Sixty consecutive patients with normal preoperative renal function undergoing elective coronary artery bypass surgery with CPB using the same anaesthetic; CPB and surgical protocols were randomized into three groups. Patients received placebo (Group 1), low-dose aprotinin (Group 2) or high-dose aprotinin (Group 3). Renal parameters measured were plasma creatinine, alpha1-microglobulin and beta-glucosaminidase (beta-NAG) excretion. Measurements were performed before surgery, during CPB and 24 and 72 h, and 7 and 40 days postoperatively. In the three groups, alpha1-microglobulin and beta-NAG excretions significantly increased during CPB, at 24 and 72 h, and 7 days postoperatively (P < 0.05) and had returned to preoperative levels at postoperative day 40. Plasma creatinine levels were within normal values at times recorded. In Groups 2 and 3, alpha1-microglobulin excretion during CPB was significantly higher than in Group 1 (P < 0.001), and 24h after surgery it still remained significantly higher in Group 3 compared to Groups 1 and 2 (P < 0.05). Aprotinin caused a significant increase in alpha1-microglobulin excretion but not in beta-NAG excretion during CPB, which may be interpreted as a greater renal tubular overload without tubular damage. This effect persisted for 24 h after surgery when high-dose aprotinin doses had been administered. Creatinine plasma levels were not sensitive to detect these prolonged renal effects in our study.

Pattern of renal dysfunction associated with myocardial revascularization surgery and cardiopulmonary bypass.

A variable incidence rate of renal dysfunction (3-35%) after cardiac surgery with cardiopulmonary bypass has been reported. The aim was to define the typical pattern of renal dysfunction that follows coronary surgery with cardiopulmonary bypass using albumin, immunoglobulin (IgG), alpha1-microglobulin and beta-glucosaminidase (beta-NAG) excretion as indicators. Twenty patients with preoperative normal renal function, defined by plasma creatinine, creatinine clearance, fractional excretion of sodium and renal excretion of proteins, undergoing elective myocardial revascularization surgery with cardiopulmonary bypass, were prospectively studied. Variables recorded were demographic and haemodynamic variables, duration of cardiopulmonary bypass and aortic clamping, intra- and postoperative urine output, plasma creatinine concentration, creatinine clearance and excretion of sodium, albumin, IgG, beta-glucosaminidase (beta-NAG), and alpha1-microglobulin. Measurements were made preoperatively, immediately before and then during and immediately after cardiopulmonary bypass, and again at 1, 24, 72 h, 7 and 40 days following surgery. Albumin and IgG excretion rose significantly during cardiopulmonary bypass (P < 0.05), remaining at these levels at 24 h postoperatively. An increase of alpha1-microglobulin and beta-NAG concentrations was observed during cardiopulmonary bypass (P < 0.05), which were maintained until the seventh postoperative day and remained elevated in some patients at the 40th postoperative day. This correlated with preoperative diabetes mellitus (P < 0.001), low cardiac output after cardiopulmonary bypass (P < 0.001) and the duration of stay in the intensive care unit (P < 0.001). The pattern of renal dysfunction after cardiopulmonary bypass for myocardial revascularization is characterized by temporary renal dysfunction at both glomerular and tubular levels with an onset within 24 h of surgery and which lasts between 24 h and 40 days, respectively, following surgery.

Low-dose dual blockade of the renin–angiotensin system improves tubular status in non-diabetic proteinuric patients

Treatment with agents that inhibit the renin-angiotensin system is commonly regarded as a gold standard renoprotective strategy in patients with chronic kidney diseases. For maximum antiproteinuric effect, the dose titration of these agents is recommended. This therapeutic strategy is not used for proteinuric patients who are not able to receive high doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonists. In patients with primary glomerulonephritis (n=24), a randomized, triple-treatment, triple-period, cross-over study was performed to compare the effects of combined therapy with benazepril 5 mg and losartan 25 mg and monotherapy with either agent alone at a two-fold higher dose on the extent of tubular injury as assessed by alpha1-microglobulin (alpha1-m) excretion and the plasma level of transforming growth factor-beta1 (TGF-beta1). Combination therapy significantly reduced alpha1-m excretion compared to either agent used alone: 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 161.59+/-23.22 mg/g creatinine for benazepril alone (p<0.05; ANOVA) and 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 173.45+/-27.69 mg/g creatinine for losartan alone (p<0.05; ANOVA). There was a significant correlation between change in alpha1-m excretion and reduction in proteinuria (r=0.704; p=0.023). There were no differences in TGF-beta1 level between the studied treatments. Systemic blood pressure reduction did not differ among the therapies. Combination therapy with angiotensin-converting enzyme inhibitor and angiotensin II subtype 1 receptor antagonists at very small doses may be superior to monotherapy with these agents at higher doses as far as tubular injury is concerned. We speculate that such a therapeutic strategy may be a useful approach for patients who are known not to be capable of receiving optimal renoprotective doses of these regimens.

Increased urinary excretion of alpha1-microglobulin at 6 months after transplantation is associated with urinary excretion of transforming growth factor-beta1 and indicates poor long-term renal outcome.

Albumin and alpha1-microglobulin (alpha1M) are absorbed by two specific receptors in tubular epithelial cells. Any cell injury will disturb the reabsorption of these proteins, The increased urinary excretions of albumin or alpha1M could thus serve as a marker of subclinical graft lesions and as an early indicator of chronic allograft dysfunction. We measured 24-hour urinary excretions of albumin, alpha1M, and transforming growth factor (TGF)-beta1 at 6 months after transplantation in 79 renal-graft recipients and recorded the changes in 24-hour creatinine clearance an average 51 (range 14-72) posttransplant follow-up months. At 6 months from transplantation, 46 of 79 (58%) patients were normoalbuminuric, 25 (32%) microalbuminuric, and 8 (10%) macroalbuminuric. In normoalbuminuric patients, urinary alpha1M/creatinine ratio was 10 times, and TGF-beta1/creatinine ratio approximately 5 times, higher than in the healthy subjects but lower than in albuminuric patients. In all patients, urinary alpha1M correlated with urinary TGF-beta1 (r=0.508, P<0.001), with albumin (r=0.220, P<0.05), and with the annual changes in 24-hour creatinine clearance (r=-0.273, P<0.05). During follow-up, renal function deteriorated in 20 of 33 (60%) patients with alpha1M/creatinine ratio greater than 5 mg/mmol, but only in 1 of 46 (2%) patients whose ratio was less than 5 mg/mmol (P<0.01), giving the ratio 5 mg/mmol or greater a 95% sensitivity to detect patients with poor long-term outcome. We show proximal tubular injury, measured by increased urinary alpha1M, to be present even in normoalbuminuric patients and to be associated with increased excretion of TGF-beta1 and with the annual deterioration of glomerular filtration rate. These findings show increased alpha1M/creatinine ratio to be an early and sensitive indicator of poor long-term outcome in renal-transplant patients.

Urinary alpha1-microglobulin excretion as biomarker of renal toxicity in trichloroethylene-exposed persons.

Concern on human renal toxicity and carcinogenicity of trichloroethylene is based on findings of increased incidences of renal cell cancers in persons with long-lasting and high occupational exposures to this solvent. The full tumour development is likely to require promotional stimuli, by repetitive episodes of high peak exposures to trichloroethylene, leading to nephrotoxicity. This process is visualised by the excretion of tubular marker proteins in the urine of exposed persons. For this purpose, surveillance of alpha1-microglobulin excretion is being suggested by the Deutsche Forschungsgemeinschaft. The present study assessed the applicability of alpha1-microglobulin as a biomarker of proximal tubule damage in the prevention of nephrotoxicity by trichloroethylene exposures. For this purpose, alpha1-microglobulin excretions were assessed in trichloroethylene-exposed and non-exposed subgroups of both cases (diseased with renal cancer) and controls (not diseased with renal cancer) of a recent case-control study. The median of alpha1-microglobulin excretions in non-exposed persons was below the detection limit, but it was clearly elevated in exposed persons. The Wilcoxon rank sum test showed a significant difference ( P=0.0090). Consistent with the underlying concept, renal cell cancer cases who had been exposed to trichloroethylene had higher alpha1-microglobulin excretions than non-exposed cases ( P=0.0005) and also had higher alpha1-microglobulin excretions than exposed controls ( P=0.0004). Of 20 trichloroethylene-exposed renal cell cancer cases only three (15%) displayed a normal alpha1-microglobulin excretion of <5 mg/l. By contrast, 41 (52%) out of 79 non-exposed renal cancer cases showed normal excretions of the biomarker. The present data are in agreement with the concept of pathogenesis of renal cell cancers developing under high (suggested: >500 ppm peak exposures) and long-term (several years) exposure to trichloroethylene. They also visualise the potential value of alpha1-microglobulin excretion as a routine biomarker of renal toxicity that may be used in the medical surveillance of trichloroethylene-exposed persons.

ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis

Cystinosis, a rare autosomal recessive disease, manifests with renal Fanconi syndrome during the first year of life. Interstitial damage is a major cause of renal failure in patients with cystinosis. We presume that albuminuria contributes to the development of renal failure in these patients. The aim of this study was to examine whether the administration of ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis. Five patients with cystinosis aged 4 - 9 years were studied. All patients had Fanconi syndrome and were treated with cysteamine. Median creatinine clearance was 48 ml/min/1.73 m2 (range 21 - 61). The excretion of albumin and alpha1 microglobulin as well as arterial blood pressure and serum creatinine were evaluated before and at 3 months on oral administration of enalapril (0.15 mg/kg once daily). At 3 months on enalapril, albuminuria decreased in all patients (1,042 vs 629 mg per 24 h, p < 0.05). The median reduction of albuminuria was 43% (range: 4 - 72%, p < 0.05). Urinary excretion of alpha1 microglobulin remained constant. Systolic blood pressure decreased from median 110 - 100 mmHg (p < 0.05), while diastolic blood pressure remained stable (median 60 mmHg). Creatinine clearance decreased from median 48 - 45 ml/min/1.73 m2 (p < 0.05) and returned to previous values after discontinuation of enalapril. ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis and might be used in these patients in order to slow the progression of renal insufficiency attributed to proteinuria.

Urinary protein and enzyme excretion as markers of tubular damage.

In this review we intend to evaluate the clinical usefulness of measurement of urinary excretion of microproteins and tubular enzymes. Studies of patients with acute tubular necrosis showed that the excretion of some well known enzymes and of new markers such as kidney injury molecule-1 has higher value than classic renal function tests for the early detection of the disease as well as for the prediction of the development of overt acute renal failure. Tubular dysfunction may be detected by measurement of the excretion of tubular enzymes and microproteins not only in workers chronically exposed to heavy metals but also in population exposed to low environmental level below the limits set by the WHO. In chronic glomerulonephritis the excretion of alpha1-microglobulin is significantly associated with the extent of tubulo-interstitial damage and predicts outcome better than proteinuria/day; in the same diseases NAG excretion is significantly dependent on immunoglobulin G and alpha1-microglobulin excretion and predicts remission, progression and response to therapy. The measurement of urinary excretion of tubular enzymes and microproteins may be clinically useful in several different kidney diseases (such as acute tubular necrosis, glomerulonephritis) both for diagnosis and prediction of fractional outcome.

Classification of renal proteinuria: a simple algorithm.

Total protein, albumin, alpha1-microglobulin, and immunoglobulin G (IgG) were analyzed in 1,622 urine samples without Bence-Jones proteinuria or gross hematuria. There was correlation with the histological picture obtained on renal biopsy in 61 patients. We established 24-h reference intervals for alpha1-microglobulin and IgG on 659 urine samples with total protein and albumin excretion rates below 100 mg/24 h and 30 mg/24 h, respectively, and creatinine clearance above 80 ml/min. The central 95% reference interval was found to be between 4 and 17 mg/24 h for alpha1-microglobulin and between 3 and 8.5 mg/24 h for IgG. In 80 urine samples with albumin excretion rate above 30 mg/24 h and alpha1-microglobulin and IgG within their reference intervals, we analyzed the 95% central interval of the distribution of the IgG/albumin ratios, and it was found to be within 0.01 and 0.20 (0.90 confidence interval: 0.17-0.24). Proteinuria was considered to be of the selective glomerular type if the albumin excretion rate was abnormal and the IgG/albumin ratio was under 0.20, even when the IgG excretion was within a pathological range. For the classification of proteinuria as predominantly tubular, we estimated the alpha1-microglobulin/albumin ratio in 173 urine samples with normal excretion rates of albumin and IgG and pathological excretion of alpha1-microglobulin. The discriminating value of 0.91 (0.90 confidence interval: 0.78-1.08) was accepted in order to define proteinuria of a tubular origin in the presence of a pathological albumin excretion rate. The association between albumin and IgG excretion rates and tubular reabsorption of the alpha1-microglobulin normally filtered by the glomerulus was studied in 33 urine samples from patients with no histologically significant tubulo-interstitial or vascular disease and a serum creatinine concentration below 141 pmol/l. The optimal curve-fitting function between albumin plus IgG and alpha1-microglobulin excretion rates was of the quadratic type (r = 0.927). Mixed proteinuria was considered when both, albumin and alpha1-microglobulin excretion rates were pathological and could not be included in the previously described groups.

Characteristics of protein excretion in patients with acute urinary retention.

To evaluate changes in protein leakage in the glomerular filtration barrier, and in the ability of the tubule to reabsorb proteins during and after acute urinary retention (AUR). Glomerular and tubular function was investigated in 24 men during AUR (mean age 68 years, mean retention time 31 h and mean retention volume 1140 mL) who were then followed for 6 months by measuring the urinary excretion of glomerular and tubular proteins, and the glomerular filtration rate (GFR). Retention was relieved by inserting a suprapubic catheter and the cause of retention treated one month later. No patient had a previous renal disease or diabetes. During AUR, and after 1 and 6 months, albuminuria was detected in 100%, 92% and 54% of patients, and increased excretion of alpha1-microglobulin in 52%, 36% and 58%, of IgG in 79%, 58% and 40%, and of IgG4 in 67%, 42% and 20%, respectively. The mean GFR was normal during retention and during the follow-up. AUR causes disturbances in both the glomerular filtration and tubular reabsorption of proteins. Albuminuria and increased excretion of IgG, IgG4 and alpha1-microglobulin occurred in most patients during AUR. After relieving retention, the albuminuria and elevated alpha1-microglobulin excretion persisted, indicating slight glomerular dysfunction and a permanent defect in the proximal tubule to reabsorb proteins. This could be caused partly by previous chronic obstruction. AUR should be relieved immediately and the basic cause treated effectively to prevent further deterioration of renal function.

Long-term renal dysfunction in patients with acute urinary retention.

Acute urinary retention (AUR) causes bilateral renal obstruction, which has been found to affect kidney function. This study evaluated both glomerular and tubular renal function in the long term after the resolution of AUR. Renal function in 15 patients affected by AUR and found still to evince renal dysfunction 6 months afterwards was re-evaluated approximately 18 months after the episode. The bladder outlet obstruction was treated and all patients voided normally at 6 month control. The percentage of patients suffering from lowered creatinine clearance and elevated alpha1-microglobulin excretion increased during follow-up from AUR up to 6 and 18 months (46% to 57% to 79% and 42% to 71% to 100%, respectively). In addition, daily protein excretion was abnormally high in 69% of patients at the 18 month follow-up. In most cases the abnormalities found in renal function were mild. Patients evincing renal dysfunction 6 months after AUR showed permanent impairment in tubular function, whereas glomerular permeability had partially recovered. Although this may be explained in part by chronic obstruction prior to AUR and although the impairment was mild in most cases, these findings stress the importance of urgent treatment of AUR to avoid the development of renal failure.