N-acetyl-beta-glucosaminidase and beta 2-microglobulin. Their urinary excretion in patients with renal parenchymal disease

The urinary excretion of N-acetyl-beta-glucosaminidase (NAG) and beta 2-microglobulin (beta 2M) was studied in 43 patients with various forms of renal parenchymal disease. Patients with membranous nephropathy, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, obstructive pyelonephritis, nephrosclerosis, and minimal change nephropathy generally had urinary NAG and beta 2M levels more than 3 SDs above those seen in normal subjects. Patients with progressive renal disease averaged higher NAG and beta 2M urinary levels than those with the same renal lesion and stable function. Since elevated urinary levels of NAG and beta 2M suggest renal tubular injury or dysfunction, our observations suggest tubulointerstitial involvement in a wide variety of renal diseases.     

Haptoglobin Prevents Renal Dysfunction Associated with Intravariceal Infusion of Ethanolamine Oleate

Endoscopic injection sclerotherapy (EIS) with ethanolamine oleate was performed in patients with esophageal varices either with (18 patients) or without (19 patients) pretreatment with haptoglobin. The serum levels of urea nitrogen, creatinine, and beta 2-microglobulin, the creatinine clearance, and the urinary levels of N-acetyl-beta-D-glucosaminidase and urinary beta 2-microglobulin were measured before and after EIS. Indices of the glomerular filtration rate (serum levels of urea nitrogen, creatinine, beta 2-microglobulin; creatinine clearance) showed no significant changes after EIS in either the haptoglobin-treated or untreated groups. However, the increase in the urinary parameters after EIS (which are indices of renal tubular function) was suppressed in the haptoglobin-treated group (p less than 0.005 for urinary beta 2-microglobulin). Our results indicated that the administration of haptoglobin has a prophylactic effect on renal tubular dysfunction associated with the use of ethanolamine oleate in EIS.     

Evaluation of kidney damage in patients with acute lymphoblastic leukemia in long-term follow-up: value of renal scan

In order to evaluate potential long-term kidney damage of childhood leukemia and risk factors affecting renal damage, we studied 116 children treated for acute lymphoblastic leukemia (ALL) using the St. Jude Total XI and XIII protocols in 1991-1998. The median follow-up period after the completion of treatment was 35 months. The following parameters were examined: urinalysis, urinary creatinine (Cr), calcium (Ca), phosphorus, beta2-microglobulin, glomerular filtration rate (GFR), tubular phosphorus reabsorption (TPR), and renal function tests. Radiological evaluation included renal ultrasonography (US), and renal scans with DMSA or MAG-3 were performed. Blood chemistry and renal US patients were normal in all patients except two. GFR, TPR, urinary Ca/Cr, beta2-microglobulin, and renal scan were abnormal in 19.0%, 16.4%, 13.8%, 6.0%, and 40.5% of patients, respectively. The abnormality rate in GFR was significantly higher in patients <2 years of age. TPR abnormality was found to be significantly higher in patients who did not have G-CSF. An abnormal renal scan was associated with Hb < 10 g/dL, kidney infiltration, or hypertension at presentation and also occurred patients who underwent methotrexate treatment with frequent intervals during the follow-up period. Patients should be followed-up after cessation of therapy with the conventional tests mentioned above. In case of any abnormality, further detailed tests should be performed; renal scan seems to be more predictive for renal damage.     

Demonstration of β2-Microglobulin in the Kidney by Direct Immunofluorescent Staining

Direct immunofluorescent staining with fluorescein isothiocyanate conjugated goat anti-human beta 2-microglobulin (beta 2M) was used to determine the localization of beta 2M in kidney tissue, obtained by biopsies or nephrectomies for various renal diseases. beta 2M was found in the renal tubular epithelial cell cytoplasm and occasionally in the tubular basement membranes in 48 out of 79 pathologic specimens tested, but not in 3 normals. beta 2M was seen in the tubular cells in all cases of primary tubulointerstitial disease and in all cases with secondary tubular damage associated with glomerular disease or systemic disease. This supports the concept that beta 2M is metabolized in proximal tubular epithelial cells, and its deposition indicates impairment of tubular handling.     

beta 2-Microglobulin levels in serum and urine of rheumatoid arthritis patients on gold therapy.

The levels of beta 2-microglobulin (beta 2-m) in serum and urine of 24 seropositive patients with rheumatoid arthritis (RA) treated with regular gold (sodium aurothiomalate) injections have been investigated. The values obtained were compared with levels from 20 seropositive patients with RA treated only with nonsteroidal anti-inflammatory drugs and 20 age and sex matched normal controls who had received no medication. A significant increase of urinary beta 2-m levels was found in the gold-treated RA group. No correlation between dose of gold received and the levels of beta 2-m in the urine could be established. There was also no correlation between the erythrocyte sedimentation rate (ESR) or total lymphocyte count and beta 2-m levels in serum or urine. We conclude that serum and urinary beta 2-m levels appear to be poor indices of joint inflammation, but sequential urinary beta 2-m levels may prove valuable in monitoring the development of renal tubular lesions due to gold therapy.     

Glomerular filtration rate and tubular involvement during acute disease and convalescence in patients with nephropathia epidemica

Glomerular filtration rate (GFR) and tubular involvement were studied in 74 patients with serologically verified nephropathia epidemica (NE). Increased levels of serum creatinine and serum beta 2-microglobulin were documented in 96% and 99% of the patients, respectively. The mean of the lowest estimated GFR was 26 ml/min. Proximal tubular reabsorptive capacity was assessed by urinary loss of beta 2-microglobulin and cell damage by urinary activity of N-acetyl-beta-D-glucosaminidase. Both of these parameters were elevated in most of the patients during the acute phase of the disease. Increased serum levels of Tamm-Horsfall-specific IgG and/or IgA occurred in 72 of 74 patients. No patient required dialysis and there was no mortality. Six months after discharge only three patients had a GFR less than 80 ml/min as estimated by [51Cr]EDTA clearance; two of these had underlying chronic diseases and one had suffered clinically severe NE. Desmopressin tests showed decreased urine osmolarity in three patients 8 months after discharge. These three had chronic diseases, which may have contributed to the impaired tubular function. Thus, there was a markedly decreased GFR and a tubular dysfunction in the acute phase of NE. Most patients recovered within a few months and none showed evidence of chronically impaired renal function due to NE.     

Effects of hip arthroplasty and peroperative dicloxacillin prophylaxis on renal function.

In a prospective pilot study 70 patients (age greater than 65 years) who underwent hip arthroplasty were treated with dicloxacillin, a total of 6 g given pre-, per- and postoperatively as antibiotic prophylaxis. Creatinine in serum and beta 2-microglobulin in serum and urine were determined as estimates of renal function. Values were obtained preoperatively and on days 2, 4 and 10 after operation. A slight but significant increase of serum creatinine was seen on day 2 with a gradual decrease almost down to the preoperative baseline value on day 10. Serum beta 2-microglobulin increased more gradually; the increase was significant on day 10. Raised levels of beta 2-microglobulin in urine were most pronounced: a 20-fold increase on day 2, then a slow decrease, still significant increase on day 10. This may indicate a reversible damage of proximal tubules with blocked tubular reabsorption of beta 2-microglobulin. The slightly increased levels of serum creatinine and beta 2-microglobulin would also indicate a minor reversible decrease in glomerular filtration rate. Whether these effects are caused by the operation trauma per se or by the dicloxacillin prophylaxis cannot be determined from this pilot study. It seems quite clear that hip arthroplasty with short term prophylaxis with dicloxacillin does not result in clinically important changes in renal function.     

Renal Metabolism of β2-Microglobulin

beta 2-microglobulin (beta 2M) is a protein of 11,800 daltons which occurs in the plasma of normal individuals at concentrations of approximately 2 microgram/ml. It is presumed to be relatively freely filterable. More than 99% of the filtered beta 2M is taken up by an active reabsorptive mechanism and catabolized by the renal tubule. The data presented here demonstrate that renal extraction is only slightly diminished by complete ureteral obstruction. The renal extraction of beta 2M is greater than can be accounted for by filtration alone. These data indicate that some uptake of beta 2M occurs from the peritubular capillary circulation. The loading of animals with beta 2M is associated with a marked tubular proteinuria suggesting that this protein may play a part in inducing tubular injury.     

Renal function and cimetidine. Urinary albumin and beta 2-microglobulin excretion and creatine clearance during cimetidine treatment

Urinary albumin and beta 2-microglobulin excretion and creatinine clearance were measured during 8 weeks' conventional cimetidine treatment in 13 ulcer patients without signs of renal disease. No changes were found in albumin or in beta 2-microglobulin excretion, indicating no changes in glomerular permeability and tubular reabsorption of proteins in the kidney. Creatinine clearance fell about 28 ml/min (26%) during cimetidine treatment but normalized after termination of medication. Concomitantly, serum creatinine increased by 22% during treatment and fell again after termination of treatment. The mechanism behind the changes in renal handling of creatinine during cimetidine was not clarified in the present study. It is concluded that the conventional 8 weeks' cimetidine treatment seems safe from the renal point of view, at least in patients without signs of renal disease.     

Glomerular and tubular proteinuria as markers of nephropathy in rheumatoid arthritis.

OBJECTIVE: We examined the prevalence of nephropathy in unselected patients with rheumatoid arthritis (RA) by measurement of marker proteins for glomerular and tubular damage in urine. METHODS: A highly sensitive immunoluminometric assay was used to measure albumin, immunoglobulin G and alpha1-microglobulin in 24 h urines of 44 RA patients and a control group of 46 patients with generalized osteoarthritis (OA). RESULTS: Fifty-five per cent of RA patients were found to have proteinuria as a symptom of renal disease. Drug therapy or vasculitis were identified as possible reasons for proteinuria in only 25% of these patients; in most patients (75%), no reason for proteinuria was found. Tubular and mixed proteinuria were more frequent than glomerular proteinuria. Only 15% of the control group exhibited mild proteinuria, which was attributable to nephrotoxic factors. The renal function of RA patients and the control group did not differ significantly. CONCLUSIONS: Proteinuria is a frequent symptom of nephropathy in RA. Screening for renal disease in RA should not only include creatinine measurement and dipstick examination of urine, but also more sensitive methods to detect tubular and glomerular proteinuria as a marker of tubular and early stages of glomerular damage.     

Comparison of serum and synovial fluid concentrations of beta 2-microglobulin and C reactive protein in relation to clinical disease activity and synovial inflammation in rheumatoid arthritis.

beta 2-Microglobulin and C reactive protein (CPR) were measured in 33 and 57 matched pairs of serum and synovial fluid (SF) respectively, from patients with active rheumatoid arthritis (RA). Serum beta 2-microglobulin concentrations were higher than in normal controls and the SF concentration was higher than the serum concentration on 25 of 33 occasions (76%), suggesting a local production of beta 2-microglobulin within the synovial membrane. There was a correlation between serum and SF concentrations of beta 2-microglobulin (r = 0.50). Patients' serum CRP concentrations in 57 samples were higher than in normal controls and were greater than in the matched SFs on 49 of the 57 paired samples (86%). In 18 samples CRP was absent in the SF, suggesting a local consumption or binding within the synovial membrane. Twenty four patients with RA given either sodium aurothiomalate or D-penicillamine for six months showed highly significant clinical improvements accompanied by reductions in serum and SF immunoglobulin concentrations and knee joint suprapatellar pouch synovial membrane T lymphocyte infiltrates. In this group of patients serum CRP, but not beta 2-microglobulin, fell significantly, but there were no significant changes in SF beta 2-microglobulin or CRP. These data suggest that serum and SF beta 2-microglobulin concentrations are not a useful index for determining the therapeutic response to sodium aurothiomalate and D-penicillamine and that serum rather than SF CRP concentrations are more helpful. The persistent raised serum and SF concentrations of beta 2-microglobulin probably reflect synovial inflammatory infiltrates, which are still considerable despite apparent clinical remission.     

Renal tubular dysfunction in Minamata disease. Detection of renal tubular antigen and beta-2-microglobin in the urine.

"Minamata disease" was found among the residents along Minamata bay contaminated with the effluent from an industrial plant using mercury. The patients were suffering from various neurologic disorders primarily due to organic mercury poisoning. Evidence is described of renal tubular dysfunction associated with this disease by the immunochemical demonstration or renal tubular epithelial antigen and beta-2-microglobulin in the urine. Nineteen patients with Minamata disease and 35 diseased and healthy control subjects were examined. The contents of urinary renal tubular epithelial antigen and beta-2-microglobulin, and the ratios of these proteins to albumin in individuals with Minamata disease were significantly different from the levels in healthy control subjects (P less than 0.05) were identical to those found in patients with tubular and the values, proteinuria. These results indicate that Minamata disease is associated with renal tubular dysfunction, and also suggest that these procedures would be useful for screening the nephrotoxicity in the environmental exposure of heavy metals.     

Kidney function tests in children with beta-thalassemia minor in Zahedan, southeast of Iran

There is little information regarding kidney function in patients with beta-thalassemia minor. In this study we investigated kidney function tests in 50 children with beta-thalassemia minor (22 boys and 28 girls). Twenty-four-hour urine samples were collected and analyzed for sodium, potassium, calcium, magnesium, creatinine, phosphate, uric acid, protein, and beta2-microglobulin. Blood samples were obtained for hematologic and biochemical analyses including complete blood count, serum ferritin, sodium, potassium, calcium, phosphate, magnesium, creatinine, and uric acid. This group of children with beta-thalassemia showed some evidence of tubulopathy such as proteinuria (32%), beta2-microglobulin excretion (36%), calciuria (4%), phosphaturia (4%), and uricosuria (20%). Our findings support the existence of renal tubular dysfunction in beta-thalassemia minor. However, further studies in large series are needed to shed light on the possible relation of these two distinct diseases.     

Glomerular and tubular renal functions after long-term medication of sulphasalazine, olsalazine, and mesalazine in patients with ulcerative colitis

To date there are only few reports evaluating the potential nephrotoxic reactions of the new 5-aminosalicylic acid (5-ASA) preparations in patients with ulcerative colitis (UC). The aim of this study was to screen the tubular and glomerular functions in patients with UC in maintenance treatment with either 5-ASA azo-compounds (sulphasalazine and olsalazine) or mesalazine. Patients with UC in clinical remission treated with either sulphasalazine, olsalazine, or mesalazine for more than 1 year were included in an open, single-blind retrospective Norwegian multicenter study. Serum and urine creatinine, serum and urine beta2-microglobulin, urine N-acetyl-beta-glucoseamidase (NAG), urine alkaline phosphatase, urine microalbumin, urine alanine amino peptidase, and urine beta2-microglobulin were measured. Fifty-two females and 75 males (n = 127), ages 20-69, were evaluated. Thirty-six patients were treated with sulphasalazine (mean treatment time 10.1+/-6.6 years [mean +/- SD]), 32 patients were treated with olsalazine (2.3+/-1.4 years), and 59 patients with mesalazine (3.2+/-2.0 years). At inclusion, there were no significant differences in the serum or urine values between the groups. In 17 patients (1 patient [3%] in the sulphasalazine group, 4 patients [13%] in the olsalazine group, and 12 patients [20%] in the mesalazine group), at least one abnormal serum and/or urine value was detected. After 10 years of treatment, only one abnormal value was found among the 19 patients in the sulphasalazine group. The abnormal values observed in the other groups indicated minor glomerular or tubular renal damage. In conclusion, long term sulphasalazine treatment appears to be safe and free of nephrotoxic side effects, whereas minor glomerular and tubular impairment are observed in a few patients treated with olsalazine and mesalazine.     

Changes in urinary retinol binding protein excretion and other indices of renal tubular damage in patients with non-insulin dependent diabetes.

Changes in urine retinol binding protein (RBP, M(r) 21,000) excretion and other indices of renal tubular damage were investigated in the patients with non-insulin dependent diabetes mellitus (NIDDM). Changes in urine RBP excretion were well paralleled with those of urine NAG excretion. In RBP-negative patients, the subjects with hypertension (systolic blood pressure > or = 140 mmHg or diastolic blood pressure > or = 90 mmHg) showed higher beta 2-microglobulin (beta 2-MG) excretion and albumin (Alb)/Cr ratios than normotensive ones. In addition, both urine beta 2-MG excretions and Alb/Cr ratios were significantly increased in RBP-positive patients. The measurement of urine RBP excretion may have an additional role in the diagnosis of renal tubular dysfunction in diabetic patients.     

Renal Surrogates in Essential Hypertension

The kidney can be considered both as culprit and victim in the hypertensive process. Renal functional derangement contributes to the development of arterial hypertension and the development of secondary vascular damage both at the glomerular and arteriolar level accounts for the development of progressive nephrosclerosis. The most common alteration of renal function observed in humans since the early stages of essential hypertension is the presence of renal vasoconstriction. This can be accompanied by the appearance of hyperuricemia, increased urinary excretion of enzymes such as N-acetyl-beta-glucosaminidase and of proteins like albumin and beta2-microglobulin. Later on, a progressive fall in glomerular filtration rate accompanied or not by proteinuria can be observed if high blood pressure persists.     

Serum beta 2-microglobulin after five-day administration of cisplatin

Patients with testicular tumors receiving the Einhorn combination chemotherapy with cisplatinum administration for five consecutive days were evaluated for signs of glomerular filtration rate impairment by means of serum beta 2-microglobulin measurements before and on days 2 and 5 after cessation of cisplatin administration and then before repeated cycles of the same chemotherapeutic regimen. Though no significant changes in the level of serum beta 2-microglobulin could be found, an evident increase in the values was seen indicating that in more aggressive cisplatin administration schedules not only tubular impairment might contribute to possible nephrotoxic effects.     

Renal dysfunction in children with uncomplicated,Plasmodium falciparum malaria in Tamale,Ghana

In a study performed in Tamale, in the Northern region of Ghana, cystatin C, a new and sensitive indicator of the glomerular filtration rate (GFR), was used to estimate the frequency of renal dysfunction in 78 children with uncomplicated, Plasmodium falciparum malaria. The excretion in urine of albumin, immunoglobulin G and alpha1-microglobulin was also investigated. Plasma concentrations of cystatin C were found to be elevated in 17% of the children, indicating subclinical impairment of renal function. As most (85%) of the children had glomerular as well as tubular patterns of proteinuria, it appears that both glomerulonephritis and damage to tubular cells often occur in P. falciparum malaria.     

Antibodies to and elevations of beta 2 microglobulin in the serum of ankylosing spondylitis patients

Antibodies to beta 2 microglobulin are found in systemic lupus erythematosus patients and are important in the lymphocytotoxic reactions of sera from such patients. In this study, beta 2 microglobulin antibodies were measured with the use of an enzyme-linked immunosorbent assay with purified beta 2 microglobulin antigen and peroxidase-labeled anti-human IgG or IgM. IgG antibodies to beta 2 microglobulin were found in 68% of 22 patients with ankylosing spondylitis. This incidence was higher than the 5% in 80 controls (P less than 0.01) and similar to the 71% incidence found in 35 patients with systemic lupus erythematosus. Eleven (27%) of 41 patients with rheumatoid arthritis had elevated levels of antibodies to beta 2 microglobulin (P less than 0.01). The mean antibody levels expressed in enzyme units were 0.125 for patients with ankylosing spondylitis, 0.157 for those with systemic lupus erythematosus, 0.101 for those with rheumatoid arthritis, and 0.067 for controls. IgM anti-beta 2 microglobulin was not significantly different from controls. A competitive binding assay with enzyme-labeled beta 2 microglobulin was used to determine serum beta 2 microglobulin. These values were also found to be elevated in 48% of patients in all 3 disease categories (P less than 0.01). Beta 2 microglobulin antibodies and serum beta 2 microglobulin did not correlate with each other, renal diseases or antinuclear antibodies in patients with systemic lupus erythematosus, with rheumatoid factor or severity of articular disease in patients with rheumatoid arthritis, or with peripheral arthritis or iritis in those with ankylosing spondylitis. Although antibodies to beta 2 microglobulin might reflect a general disturbance of immune regulation in patients with systemic lupus erythematosus, their presence in those with ankylosing spondylitis, a disease closely associated with a specific HLA allotype and not usually associated with formation of autoantibody, suggests that they might play a role in the pathogenesis of the latter disease.     

Significance of β2-Microglobulin in Liver Diseases

Serum levels of beta 2-microglobulin (beta 2-M) were found to be significantly elevated in acute viral hepatitis, chronic persistent or active hepatitis and liver cirrhosis. beta 2-M values were significantly lower in chronic persistent hepatitis than in the three other groups. Serum beta 2-M was normal in 75 asymptomatic carriers of HBsAg. Steroid therapy was followed by reduction of serum beta 2-M levels in 11 cases of chronic active hepatitis. Variations of beta 2-M were independent from that of transaminases, bilirubin and gamma-globulins.