Relation between immunocytological features of bronchoalveolar lavage fluid and clinical indices in sarcoidosis.

This study was designed to determine whether cell populations in bronchoalveolar lavage fluid represent a reflection of disease activity in sarcoidosis. Bronchoalveolar lavage fluid cells were obtained from 22 patients with sarcoidosis and from 10 normal control subjects and investigated by immunocytological methods. A panel of monoclonal antibodies was used to determine the relative proportions of phenotypically distinct subsets of macrophages and lymphocytes in the patients with sarcoidosis and to correlate them with clinical indices, such as disease duration, serum angiotensin converting enzyme, the chest radiograph, and results of pulmonary function tests. Patients with sarcoidosis had a higher percentage than the normal subjects of macrophage like cells expressing RFD1 (a class II associated antigen preferentially expressed by dendritic cells), an epithelioid cell antigen (RFD9), and a circulating monocyte antigen (UCHMI). The increase in RFD1+ cells appeared to be due to detection of antigen by this antibody on cells that were also expressing phenotypic markers of classical tissue macrophages (RFD7). The lymphocytes in lavage fluid from patients with sarcoidosis were characterised by increased expression of activation markers, such as interleukin-2 receptors (anti-Tac+), HLA-DR (RFDR+), and "blast" forms (expressing above normal concentrations of CD7 antigen). This was associated with increased proportions of the CD4+ (helper-inducer) T cell subset. Patients with sarcoidosis whose clinical indices suggested activity showed an increased number of macrophages coexpressing RFD1 and RFD7 antigens, of macrophages expressing UCHM1 and lymphocytes expressing activation markers. The expression of these markers was also increased on lavage cells from patients with radiographic evidence of widespread disease (chest radiographic stage II and III), but there was no relation with disease duration, pulmonary function, or serum angiotensin converting enzyme activity. Immunocytological analysis of lavage cells offers a probe for studying the pathogenesis of sarcoidosis and may be of value in monitoring disease activity.     

Release of prostaglandin E2 and leukotriene B4 by alveolar macrophages from patients with sarcoidosis

BACKGROUND: Mediators released by alveolar macrophages, as well as by T cells, play an important part in modulating local immune processes in sarcoidosis. Among alveolar macrophage secretory products, arachidonic acid metabolites are known to regulate inflammatory and immune reactions. It has been suggested that cyclo-oxygenase and lipoxygenase pathway metabolites of arachidonic acid modulate the evolution of the granulomatous inflammatory response in the lung differently. METHODS: Alveolar macrophages recovered from the bronchoalveolar lavage (BAL) fluid of 32 patients with sarcoidosis in different states of disease activity and 10 normal subjects were evaluated for their ability to release prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). Alveolar macrophages were cultured in the presence or absence of opsonised zymosan (500 micrograms/ml), and PGE2 and LTB4 levels in the culture supernatants were determined by enzyme immunoassay (EIA). RESULTS: Stimulated alveolar macrophages from patients with active sarcoidosis released higher LTB4 levels than those from normal subjects, but no differences in PGE2 release were observed between the two groups. The time course of LTB4 release by activated alveolar macrophages showed that normal cells produced similar levels of the hydroxyacid during the early and late times of culture while LTB4 release by activated cells from patients with sarcoidosis increased markedly after 60 minutes of culture, remaining elevated until 24 hours. Indomethacin (3 x 10(6) M) caused the expected inhibition of PGE2 formation without affecting LTB4 release. CONCLUSIONS: These results suggest that alveolar macrophages from the BAL fluid of patients with active sarcoidosis are primed to release LTB4, which may contribute to the locally heightened immune response.




     

Collagenase and fibronectin in bronchoalveolar lavage fluid in patients with sarcoidosis

Bronchoalveolar lavage fluid from 43 patients with biopsy proved sarcoidosis and 10 control subjects were assayed for fibronectin and collagenase activity. Fibronectin was significantly increased in the group with sarcoidosis and was found to be positively correlated with angiotensin converting enzyme activity, protein concentration, percentage of T cells and helper:suppressor ratios in the lavage fluid. Increased fibronectin in the bronchoalveolar lavage fluid was not related to functional or radiographic indices of interstitial disease and did not identify patients subsequently requiring treatment. Latent collagenase was present in bronchoalveolar lavage fluid from 16 patients with sarcoidosis but not in any control sample. There was no association between the collagenase activity and the cell profiles of the lavage fluid. Yet carbon monoxide transfer factor was decreased in patients with bronchoalveolar lavage fluid collagenase. Ten of 16 patients with bronchoalveolar lavage fluid collagenase had radiographic class III or IV disease and a disease duration of more than two years. On follow up 62% of patients with bronchoalveolar lavage fluid collagenase required subsequent treatment, compared with only 23% of patients without collagenase. These results indicate an association between bronchoalveolar lavage fluid collagenase and progressive, prolonged disease in sarcoidosis, whereas increased bronchoalveolar lavage fluid fibronectin is associated with indices of disease activity.     

Intercellular adhesion molecule 1 (ICAM-1) in the pathogenesis of mononuclear cell alveolitis in pulmonary sarcoidosis.

BACKGROUND--Alveolitis in pulmonary sarcoidosis is characterised by an accumulation of highly activated macrophages and CD4+ lymphocytes in the alveolar compartment. The role of intercellular adhesion molecule 1 (ICAM-1) expression on alveolar cells has been studied in this context. METHODS--Using a sandwich ELISA technique, ICAM-1 expression on alveolar macrophages from 17 consecutive untreated patients with pulmonary sarcoidosis and six healthy normal volunteers was quantified. In addition, parameters of macrophage activation (tumour necrosis factor alpha (TNF alpha) and superoxide anion release) were evaluated. RESULTS--Significantly elevated expression could be demonstrated on alveolar macrophages from patients with pulmonary sarcoidosis compared with healthy controls (mean (SD) 0.74 (0.24) ELISA units (EU) v 0.46 (0.12) EU). On subdividing the patients into those with active and those with inactive disease, only the former showed increased ICAM-1 levels on alveolar macrophages (0.82 (0.27) EU) compared with control alveolar macrophages. No differences were detected in serum levels of soluble ICAM-1 between patients and controls. ICAM-1 expression on alveolar macrophages from patients with sarcoidosis correlated with the spontaneous release of TNF alpha but not with the release of the superoxide anion by the activated macrophages. There was no correlation with the percentage of lymphocytes or the absolute number of CD4+ cells in bronchoalveolar lavage fluid. CONCLUSIONS--Increased ICAM-1 surface expression on alveolar macrophages reflects disease activity in the pulmonary compartment. Considering the significance of adhesion molecules during antigen presentation and lymphocyte activation, ICAM-1 expression on alveolar macrophages may have an important role in the immune process of pulmonary sarcoidosis.     

Analysis of restriction fragment length polymorphism for the HLA-DR gene in Japanese patients with sarcoidosis.

BACKGROUND--It is commonly assumed that some immunological disorder may play a part in the pathogenesis of sarcoidosis. Previous studies by several groups have shown a significant association with HLA-DR antigens in patients with sarcoidosis. In this study, restriction fragment length polymorphism (RFLP) analysis of the HLA-DR gene was designed to confirm the association at the gene level and to look for a gene rearrangement which may influence susceptibility to sarcoidosis. METHODS--Thirty two unrelated Japanese patients with sarcoidosis were tested for HLA antigens and subjected to RFLP analysis after digestion with Eco RI, Pst I, Bam HI, Pvu II, and Hind III by using an HLA-DR beta cDNA probe. A group of 47 unrelated healthy Japanese subjects served as controls. Frequencies of each restriction fragment were compared between the patients and the control subjects. Correlation between fragment frequencies and clinical features were also analysed. RESULTS--No restriction fragments of HLA-DR beta gene were found specific to the patients with sarcoidosis. The RFLP analysis could detect polymorphism of HLA-DR beta genes that was not distinguishable by conventional serological methods. Several restriction fragments of the DR beta gene were seen only in DRw52 positive individuals, and showed higher frequencies in the patients than in control subjects. The patients with these DNA fragments were likely to have limited stage disease with no ophthalmic involvement. CONCLUSIONS--An association between HLA and sarcoidosis was noted at the DNA level, although no restriction fragments were specific for this disease. RFLP analysis of the HLA gene is a more useful method than the usual HLA typing, and should be the first step in identifying the gene sequence which is connected with susceptibility to sarcoidosis.     

Correlation between the severity of clinicopathological parameters and whole blood interferon-alpha production capacity in active phase IgA nephropathy patients.

BACKGROUND/AIMS: Patients with IgA nephropathy (IgA-N) are thought to have immune system disorders that frequently result in high serum IgA levels and a relatively high susceptibility to upper respiratory infections. AIMS: To clarify the influence of the specific immune response of IgA-N patients on the clinicopathological features of the disease, we measured the whole-blood-producing capacity of interferon-alpha (IFNalpha-PC). We then compared these findings with clinical and histopathological parameters, including tissue macrophage infiltration, during both histologically active and latent phases. PATIENTS AND METHODS: Fifty-one inpatients with IgA-N and 70 healthy controls were examined. According to the histological findings, 32 patients had disease in the active phase (AP), and 19 were in the latent phase (LP). RESULTS: In AP patients, IFNalpha-PC showed positive correlations to serum creatinine, blood urea nitrogen, serum beta2-microglobulin (s-beta2MG), urinary total protein (U-TP), and urinary beta2MG, in addition to the number of infiltrated macrophages per area of interstitium. In LP patients, negative correlations were shown between IFNalpha-PC and s-beta2MG, U-TP, and U-N-acetyl-beta-D-glucosaminidase. CONCLUSION: A significant positive relationship exists between IFNalpha-PC and the clinicopathological parameters of deteriorated renal lesions in the AP but not in the LP. Thus, the immune status influencing the functional damage may differ between these two phase.     

Diagnostic value of serum angiotensin converting enzyme activity in lung diseases.

Serum angiotensin converting enzyme (ACE) activity was measured in 10 patients with early active sarcoidosis, nine patients with inactive or resolving sarcoidosis, 10 patients with malignant pulmonary neoplasms, eight patients with miscellaneous lung diseases, and 18 control subjects with no known pulmonary disease. The serum ACE activity, expressed in units/ml, in control subjects (5-88 +/- 1-84), was no different from the values obtained in patients with inactive or resolving sarcoidosis (6-85 +/- 2-48) or miscellaneous lung diseases (4-61 +/- 3-20). However, the ACE activity was found to be markedly raised in patients with early active sarcoidosis (13-49 +/- 2-52), and there was no overlap with control values. The patients with pulmonary neoplasms had significantly lower values of serum ACE activity than the control subjects (2-80 +/- 3-30).     

Inflammatory cell infiltration around beta 2-microglobulin amyloid deposition: histologic comparison of beta 2-microglobulin amyloidosis with AA or AL amyloidosis]

Thirty-one autopsy cases of beta 2-microglobulin (beta 2M) amyloidosis were pathologically investigated in comparison with 17 autopsy cases of AA or AL amyloidosis. In 20 cases (65%, 20/31) of beta 2M amyloidosis, inflammatory cells, mainly macrophages were seen infiltrating around beta 2M amyloid in intervertebral disks. The more beta 2M amyloidosis advances, the more macrophage infiltration tends to be prominent. In cases of severe beta 2M amyloidosis, the cytoplasm of macrophages around amyloid deposition were swollen with engulfed amyloid substance and were often transforming to foreign body multinucleated giant cells. In addition, granulation tissue was formed with infiltrating macrophages, foreign body multinucleated giant cells, capillary proliferation and fibrosis around beta 2M amyloid deposition. On the other hand, inflammatory cell infiltration around amyloid deposition was scarcely seen in AA or AL amyloidosis. Ultrastructurally, macrophages were abundant in phagocytic vacuoles containing amyloid fibrils. These macrophages were immunohistochemically positive for CD68, IL-1 beta and TNF-alpha. Thus, macrophage infiltration around beta 2M amyloid is thought to be responsible for local pain and tissue destruction of dialysis patients.     

Immune status and immune therapy of renal cell carcinoma

At present, no sufficient therapy for metastatic renal cell carcinoma is available. Several immunotherapeutical protocols have been studied, success rates, however, were inconsistent. The purpose of this study was to assess the pretherapeutic immunological status of 13 patients with metastatic and 16 patients with nonmetastatic renal cell carcinoma and of 15 healthy volunteers. Determined were differential blood counts, lymphocyte subpopulations, beta 2-microglobulin, tumor necrosis factor (TNF), neopterin, immunoglobulin, fibronectin and ferritin. Additionally, these parameters were recorded for monitoring an immunotherapeutical approach with the xenogeneic biological response modifier Keyhole limpet hemocyanine (KLH) in 10 patients with metastatic and in 5 patients with nonmetastatic disease. The pretherapeutic immunological status of patients with metastatic disease was characterized by significantly reduced T4-, T8- and B-cell counts. Significantly increased were granulocyte counts, beta 2-microglobulin, neopterin and TNF. In patients who did not suffer from metastases, only beta 2-microglobulin and neopterin were increased significantly. During immunotherapy, in patients with metastases, there was a decline of lymphocyte subsets and of the T4/T8-ratio, which correlated with progress of the disease. Humoral immune parameters showed no changes compared to pretherapeutic values. In patients who did not suffer from metastases, cellular immune parameters showed stable values during immunotherapy; neopterin, beta 2-microglobulin and TNF increased considerably. These findings indicate immunosuppression in patients with metastatic renal cell carcinoma, increasing with progression of the disease and possibly impairing the immunostimulating effects of biological response modifiers during immunotherapy. In conclusion, the clinical response of metastatic renal cell carcinoma to immunotherapy might be improved if the immunostimulant is combined with agents suitable to overcome immunosuppression, i.e. low doses of cyclophosphamide or inhibitors of prostaglandin synthesis. In addition, assessment of immune parameters for monitoring the actual immune status of a patient and the immunological effects of therapy was found to be a necessary part of immunotherapy.     

Calcium and Vitamin D in Sarcoidosis: Is Supplementation Safe?

Granulomas in sarcoidosis express high levels of 1α‐hydroxylase, an enzyme that catalyzes the hydroxylation of 25‐OH vitamin D to its active form, 1,25(OH)₂ vitamin D. Overproduction of 1α‐hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first‐line treatment in organ‐threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25‐hydroxy vitamin D (25‐(OH)D), 1,25‐dihydroxy vitamin D (1,25(OH)₂D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25‐(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD‐supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D–deficient sarcoidosis patients should be supplemented. © 2014 American Society for Bone and Mineral Research.     

Amyloid urinary-tract calculi in patients on chronic dialysis

Urinary calculi found in 4 patients on chronic hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) were identified as protein calculi by infrared spectroscopic analysis. Positive Congo red staining and immunological assessment revealed that the calculi were composed of amyloid protein derived from beta 2-microglobulin. A comparison of the patients who excreted calculi with 10 patients on chronic dialysis without urinary calculi showed no significant differences in the urinary and serum levels of beta 2-microglobulin. The mechanism of amyloid calculus formation may involve factors independent of the concentration of beta 2-microglobulin in urine or serum. Urinary calculi found in patients on chronic hemodialysis or CAPD were composed of amyloid protein derived from beta 2-microglobulin.     

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis

BACKGROUND—Serum angiotensin converting enzyme(SACE) is considered to reflect disease activity in sarcoidosis. SACEactivity is increased in many patients with active sarcoid lesions. Themechanism for the increased SACE activity in this disease has not beenclarified. ACE insertion/deletion (I/D) gene polymorphism has beenreported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of theassociation of angiotensin II receptor gene polymorphisms withsarcoidosis was therefore undertaken.
METHODS—ACE (I/D), angiotensin II type 1 receptor(AGTR1), and angiotensin II type 2 receptor (AGTR2 ) gene polymorphismswere investigated by polymerase chain reaction (PCR) and SACE levelswere measured in three groups of patients: those with sarcoidosis ortuberculosis and normal controls.
RESULTS—There was no difference in allelefrequency of AGTR1 and AGTR2 polymorphism among the three groups.Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis.SACE activity was higher in patients with sarcoidosis with the AGTR1A/C genotype than in others. However, this tendency was not detected inpatients with tuberculosis.
CONCLUSIONS—The AGTR1 allele C is associated withhigh activity of SACE in patients with sarcoidosis. It is anotherpredisposing factor for high levels of SACE in patients withsarcoidosis and is considered to be an independent factor from the ACED allele for high levels of SACE in sarcoidosis. This fact could be oneof the explanations for the increased SACE activity in sarcoidosis.

     

Does serum angiotensin converting enzyme reflect intensity of alveolitis in sarcoidosis?

Serum angiotensin converting enzyme activity is increased in many patients with pulmonary sarcoidosis and has been proposed as a measure of disease activity. Assay of serum angiotensin converting enzyme, bronchoalveolar lavage, and gallium scans were performed in 27 patients with biopsy proved pulmonary sarcoidosis. There was a positive correlation between serum angiotensin converting enzyme activity and an index of pulmonary gallium uptake assessed by the National Institutes of Health method (r = 0.7, p less than 0.001). There was no significant relationship (r = 0.19) between serum angiotensin converting enzyme activity and bronchoalveolar lavage lymphocytes expressed as a proportion of cells recovered. Increase in the enzyme activity had a sensitivity of 50% as a means of detecting high intensity alveolitis but specificity was only 45%. There was no significant difference in mean angiotensin converting enzyme activity between the following groups: those with positive and those with negative gallium scans; those with bronchoalveolar lavage lymphocyte counts less than or equal to 28% and those with counts greater than 28%. Although there was a significant correlation between the enzyme activity and one component of the alveolitis of sarcoidosis, the data suggest that serum angiotensin converting enzyme activity alone is neither sensitive nor specific enough for high intensity alveolitis.     

Renal handling of beta-2-microglobulin in renal disorders: with special reference to hepatorenal syndrome

A study of serum beta 2-microglobulin and urinary beta 2-microglobulin in patients with liver and/or kidney disease was done to determine if such information is of diagnostic help. Serum concentrations and beta 2M/Cr clearance ratios are higher in patients with primary tubular disorders than in those with glomerular diseases, a finding unaltered by hepatic disease. These data suggest either an increased production or decreased tubular degradation of beta 2M, independent of the glomerular filtration rate (GFR), in primary tubular disorders. The marked increase in urinary beta 2-microglobulin that followed insertion of the peritoneal-jugular shunt is evidence that this procedure resulted in improvement of the GFR, in previously underperfused nephrons.     

The beta2-microglobulin/cystatin C ratio--a potential marker of post-transplant lymphoproliferative disease

BACKGROUND: As a consequence of more intensified immunosuppression, post-transplant lymphoproliferative disease (PTLD) is increasingly observed in patients after solid-organ transplantation. Beta2-microglobulin, a low-molecular weight protein (MW 11.8 kDa), is produced by all nucleated cells as part of the HLA complex. Its serum concentration is directly correlated with prognosis in patients with lymphatic neoplasms. Like other low-molecular weight proteins, beta2-microglobulin is eliminated by glomerular filtration. This complicates its use as a tumor marker in renal insufficiency. Cystatin C, a low-molecular weight protein of 13.3 kDa, is a new marker of kidney function largely unaffected by extrarenal disease. We, therefore, sought to assess the potential of the beta2-microglobulin/cystatin C ratio (beta2M/Cys) as a marker of lymphoproliferation. PATIENTS AND METHODS: Beta2M/Cys was determined by particle-enhanced immunonephelometry in sera from 132 children with different degrees of renal insufficiency, 5 of whom had lymphoproliferative disease. Renal function was assessed using the Schwartz formula. RESULTS: Beta2M/Cys was constant between 1.2 and 2.4 mg/mg for Schwartz GFR > or = 40 ml/min x 1.73 m2. With lower GFR, beta2M/Cys rose progressively, maximum values being found in the hemodialysis patients (4.85-11.73). Healthy renal transplant recipients had beta2M/Cys comparable to controls. With acute lymphoproliferative disease, all but one patient had significantly elevated beta2M/Cys between 2.68 and 3.68 mg/mg, which returned to normal in remission (1.67-2.35 mg/mg). The sensitivity of a beta2M/Cys ratio > 2.4 mg/mg for the detection of PTLD was 80%, the specificity 100%, positive predictive value 100%, negative predictive value 90%. CONCLUSION: The beta2-microglobulin/cystatin C ratio is a promising parameter of lymphoproliferation in patients with normal or mildly impaired renal function.     

Usefulness of serum cystatin-C as a marker of the renal function: a comparative evaluation with beta 2-microglobulin, alpha 1-microglobulin and creatinine

We evaluated the usefulness of cystatin-C as a marker of renal function. Serum cystatin-C level was measured using latex agglutination tests in 885 patients with various forms of renal disease and 200 healthy subjects. In addition to cystatin-C, serum beta 2-microglobulin, alpha 1-microglobulin and serum creatinine (Scr) were measured concomitantly in the same sample. The serum cystatin-C level inversely correlated more closely with creatinine clearance (Ccr) (r = -0.90) than serum beta 2-microglobulin (r = -0.85), alpha 1-microglobulin (r = -0.74) and Scr (r = -0.78). In patients with mildly impaired renal function (defined as Ccr 71-90 ml/min), a significant increase in cystatin-C level was observed in 24% of patients, whereas elevated beta 2-microglobulin and Scr were seen in 8% and elevated alpha 1-microglobulin was seen in 17%. In patients with normal renal function (defined as Ccr > or = 100 ml/min), increased cystatin-C level was observed in 7% of patients, whereas beta 2-microglobulin was seen in 2%, Scr in 2% and alpha 1-microglobulin in 11%. These data suggest that cystatin-C is a better marker of glomerular filtration than beta 2-microglobulin, alpha 1-microglobulin and Scr. Moreover cystatin-C measurement offers improved clinical sensitivity as a screening test for early renal damage.     

Mild renal injury in Behçet's disease

AIM: The aim of this study is to investigate the frequency of microalbuminuria and abnormal urinary beta2-microglobulin excretion in patients with Beh?et's disease (BD). MATERIALS AND METHODS: Twenty-eight patients and 27 healthy controls were included in this study. Urine albumin/creatinine and beta2-microglobulin/creatinine ratios were calculated. RESULTS: The frequency of microalbuminuria and abnormal urinary beta2-microglobulin excretion was higher among patients with BD than in control group, but this was not statistically significant (p > 0.05). CONCLUSION: Microalbuminuria and abnormal beta2-microglobulin excretion are markers of renal injury, which have not been investigated in BD previously. Renal injury in BD is more frequent than has been recognized and it is most often in mild nature.     

Serum beta 2-microglobulin as a index of the initiation of dialysis therapy for diabetic patients with chronic renal failure]

This study was designed whether serum beta 2-microglobulin is good index for the initiation of dialysis therapy in diabetic patients with chronic renal failure. Serum creatinine (S. Cr), beta 2-microglobulin (S. beta 2-MG) and guanidinoacetic acid (S. GAA) were measured in dialyzed or undialyzed diabetic patients with chronic renal failure in comparison with non diabetic patients. 28.6% of diabetic patients showed S. Cr below 8.0 mg/dl at the initiation of dialysis therapy although all of non diabetic patients showed it over 8.0 mg/dl. On the other hand, there was no significant difference in S. beta 2-MG between diabetic and non diabetic patients, and all patients of the two groups showed S. beta 2-MG over 12.0 mg/l. In non diabetic patients whose S. Cr was below 8.0 mg/dl, undialyzed patients had a significant correlation between S. Cr and S. beta 2-MG (r = 0.840, P less than 0.01), and all non diabetic patients showed relatively high value of S. Cr as compared with that of beta 2-MG at the initiation of dialysis therapy. Undialyzed diabetic patients whose S. Cr was below 8.0 mg/dl also revealed a close correlation between serum creatinine and beta 2-MG (r = 0.864, P less than 0.01), but dialyzed diabetic patients showed different correlation between S. Cr and S. beta 2-MG from it of non diabetic patients and S. Cr was underestimated as compared with S. beta 2-MG. Undialyzed diabetic patients showed significant lower values of S. Cr and S. GAA of non diabetic patients whose S. beta 2-MG were almost same as diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

New aspects of the renin-angiotensin system: angiotensin-converting enzyme 2 - a potential target for treatment of hypertension and diabetic nephropathy

PURPOSE OF REVIEW: Whereas angiotensin-converting enzyme promotes the formation of angiotensin II, angiotensin-converting enzyme 2 promotes the degradation of angiotensin II to angiotensin-(1-7). We review recent studies dealing with angiotensin-converting enzyme 2 in kidney disease and hypertension, and discuss the potential therapeutic benefit of increasing angiotensin-converting enzyme 2 activity in the treatment of these diseases. RECENT FINDINGS: In glomeruli from diabetic mice, angiotensin-converting enzyme 2 expression is downregulated, and pharmacological inhibition of angiotensin-converting enzyme 2 leads to worsening of albuminuria, increased mesangial matrix deposition and fibronectin expression. The deletion of the angiotensin-converting enzyme 2 gene in mice leads to worsening of angiotensin II-induced hypertension and has also been shown to cause glomerulosclerosis in aging male mice. SUMMARY: Angiotensin-converting enzyme 2 is a key enzyme in the renin-angiotensin system that favors the degradation of angiotensin I and angiotensin II. Angiotensin-converting enzyme 2 inhibition by pharmacological means and by genetic deletion worsens kidney disease in diabetic mice. Strategies geared to increasing angiotensin-converting enzyme 2 activity may provide a novel therapeutic target within the renin-angiotensin system by enhancing angiotensin II degradation that may complement the current approach of inhibiting angiotensin II formation and action. Amplifying angiotensin-converting enzyme 2 activity may have a potential therapeutic role for kidney disease and hypertension.     

Familial progressive renal tubulopathy.

We report herein data on 6 male patients with progressive tubulopathy. These patients belonged to two families: the propositus, his father, a paternal first cousin, two paternal uncles, and a maternal uncle. A 7-year-old proband had mild proteinuria (1 g/day), consisting of beta 2-microglobulin, alpha 1-microglobulin and lysozyme, and aminoaciduria. Glycosuria and acidosis were absent. A 38-year-old father had mild proteinuria (2 g/day), including low-molecular-weight protein. Hypokalemia, hypophosphatemia, glucosuria, phosphaturia, aminoaciduria, and reduced urinary concentrating ability were also present. The other 4 affected family members also had low-molecular-weight proteinuria, detected by screening for beta 2-microglobulin. In addition, there were several abnormalities; aminoaciduria in all 6, phosphaturia in 4 of 6, hypercalciuria in all 6 and glycosuria in 2 of 6 patients. Tubular dysfunction was more severe in the older subjects, hence, the disease seems to progress with age. Familial low-molecular-weight proteinuria is apparently a progressive disease linked to a X-linked or to an autosomal dominant inheritance.