Characteristics of acute glomerulonephritis associated with human parvovirus B19 infection.

BACKGROUND: Acute glomerulonephritis (AGN) is a rare complication of human parvovirus B19 (HPB19) infection. The clinical and pathological features of AGN associated with HPB19 (HPBAGN) have not yet been fully elucidated. METHODS: We analyzed 10 HPBAGN cases, focusing on their clinical and serological features. We also performed histopathological examinations of renal biopsy specimens obtained from three of the 10 patients on day 15, 19 and 23, respectively, after the onset of symptoms. The phenotype of the glomerular infiltrating leukocytes in HPBAGN was determined by immunohistochemical staining and compared with that of glomerular infiltrating leukocytes in poststreptococcal AGN (PSAGN) and lupus nephritis. RESULTS: The clinical course and laboratory data of the HPBAGN patients revealed female preponderance (male = 0, female = 10), erythema in 9 of the 10 patients, leukopenia in 3, positive antinuclear antibody titer in 4, hypocomplementemia with low levels of C3, C4, and CH50 in 9, and liver dysfunction in 7. Endocapillary hypercellularity of leukocytes was demonstrated in all three patients who underwent renal biopsy. In comparison with PSAGN and lupus nephritis with crescents there were less neutrophil in HPBAGN compared to marked macrophage infiltrates that were equally intense in both the control and the HPBAGN group. CONCLUSIONS: Our findings indicate that HPBAGN is characterized by female preponderance, erythema, leukopenia, positive antinuclear antibody titer, and hypocomplementemia, and that minor neutrophil infiltration may be related to mild clinical manifestations despite the marked fixation of glomerular leukocytes in HPBAGN.

Steroid pulse therapy combined with tonsillectomy in IgA nephropathy associated with diabetes mellitus.

Ten patients with biopsy-confirmed IgA nephropathy associated with diabetes mellitus underwent dietary weight control and three courses of intravenous pulses of methylprenisolone followed by prednisolone for 6-12 months and tonsillectomy. The average length of the follow-up period was 47.8 (range 30-96) months. As compared with pretreatment values, hematuria, proteinuria, body mass index, and hemoglobin A(1c) were significantly improved after treatment. There were no significant differences with regard to blood pressure and glycemic blood glucose control. There was no worsening of diabetic retinopathy and nephropathy. During steroid pulse therapy, the patients who were treated with insulin needed a higher dosage of insulin; after steroid pulse therapy, the dosage returned to baseline. Even patients with IgA nephropathy and diabetes mellitus could be treated with combined therapy and showed beneficial responses, it they succeeded in reducing body mass index.

Tonsillectomy and steroid pulse therapy significantly impact on clinical remission in patients with IgA nephropathy.

We conducted a retrospective investigation of renal outcome in 329 patients with immunoglobulin A (IgA) nephropathy with an observation period longer than 36 months (82.3 +/- 38.2 months) in our renal unit between 1977 and 1995. Clinical remission, renal progression, and the impact of covariates were estimated by Kaplan-Meier analysis and a Cox regression model. In 157 of 329 patients (48%), disappearance of urinary abnormalities (clinical remission) was obtained. None of these 157 patients showed progressive deterioration, defined as a 50% increase in serum creatinine (Scr) level from baseline, during the observation period. Conversely, in patients without clinical remission, the Kaplan-Meier estimate of probability of progressive deterioration was 21% +/- 5% at 10 years. In the multivariate Cox regression model with 13 independent covariates, initial Scr level, histological score, tonsillectomy, and high-dose methylprednisolone therapy had a significant impact on clinical remission, whereas proteinuria, age, sex, levels of hematuria, blood pressure, conventional steroid therapy, angiotensin-converting enzyme inhibitor therapy, and cyclophosphamide therapy had no significant effect. These findings indicate that interventions aimed at achieving clinical remission have provided encouraging results applicable to managing patients with IgA nephropathy.

Autonomic insufficiency as a factor contributing to dialysis-induced hypotension.

BACKGROUND: Autonomic insufficiency is considered a factor that contributes to dialysis-induced hypotension (DIH). However, the relationship between the two conditions has not been fully elucidated. METHODS: We investigated 44 haemodialysis patients using [(123)I]-meta-iodobenzylguanidine (MIBG) scintigraphy and power-spectral analysis (PSA) of heart rate variability. The patients were divided into four groups: a diabetic group with DIH, a diabetic group without DIH, a non-diabetic group with DIH, and a non-diabetic group without DIH. In these groups the heart to mediastinum average count rate (H/M), MIBG washout rate, and low- and high-frequency components of PSA were compared. RESULTS: From the [(123)I]-MIBG scintigraphy, for both early and delayed images, H/M of the groups with DIH were lower than in groups without DIH, in both diabetics and non-diabetics (P<0.05). For the early images, H/M of the diabetic groups were lower than in the non-diabetic groups, in the groups both with and without DIH (P<0.01). For the delayed images, H/M of the diabetic group was lower than in the non-diabetic group, in the groups with DIH (P<0.05). The MIBG washout rate was the highest in the diabetic group with DIH (P<0.05 vs diabetic and non-diabetic groups without DIH). The PSA of heart rate variability showed a good discrimination of the low-frequency component between the non-diabetic patients with and without DIH (P<0.05). Mean ultrafiltration volume and its rate were not different among the four groups. CONCLUSION: Autonomic insufficiency is more severe in patients with DIH than in those without, and its degree may be enhanced in diabetic patients. For the management of DIH, special care should be addressed not only to dry weight but also to autonomic insufficiency.

Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation.

BACKGROUND: Several families have been described in which an A to G transition mutation at position 3243 (A3243G) of the mitochondrial DNA (mtDNA) is associated with focal and segmental glomerulosclerosis (FSGS). However, the prevalence, clinical features, and pathophysiology of FSGS carrying mtDNA mutations are largely undefined. METHODS: Among 11 biopsy-proven primary FSGS patients of unknown etiology, we examined seven FSGS patients to determine whether any of the clinical and pathological features of FSGS were associated with an A3243G mtDNA mutation. In four subjects in whom the A3243G mtDNA mutation was discovered in blood leukocytes, as well as in urine sediments, we retrospectively reviewed the medical records and re-evaluated the renal biopsy specimen using light and electron microscopy. We further screened the patient's family members for the presence and degree of heteroplasmy for this mtDNA mutation and obtained medical histories that were consistent with mitochondrial cytopathy. RESULTS: The four individuals identified with the A3243G mtDNA mutation were female. Proteinuria was diagnosed in these individuals during a routine annual health checkup in their teenage years. None of the patients showed any symptoms related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode, whereas diabetes mellitus in two of the patients and a hearing disturbance in one patient became manifest within a 3- to 13-year follow-up period. Strict maternal transmitted inheritance was confirmed by pedigree studies in all of these patients. Steroid therapy was ineffective in all four patients. In two of these patients, renal function declined slowly to end-stage renal failure. Histologic examination of biopsy specimens revealed that glomeruli were not hypertrophied, while electron microscopic examination identified severely damaged, multinucleated podocytes containing extremely dysmorphic abnormal mitochondria in all patients. CONCLUSIONS: FSGS may belong to the spectrum of renal involvement in A3243G mtDNA mutation in humans. Severely injured podocytic changes containing abnormal mitochondria may explain the pathogenesis of FSGS in association with the A3243G mtDNA mutation.

Urinary macrophages as activity markers of renal injury.

The presence of macrophages (Mφ) in the urine of patients with glomerulonephritis (GN) reflects the pathological events in the kidney, and we have discovered the following correlations between the Mφ phenotype and the pattern of renal injury. (1) Urinary macrophage (Mφ) counts increase in patients with proliferative GN, especially in the presence of active glomerular lesions (glomerular tuft necrosis, crescent, and endocapillary proliferation). In patients with hematuria, a combination of urinary Mφ and T-lymphocyte counts can be used to differentiate proliferative GN from non-proliferative renal disease (hereditary nephropathy and idiopathic renal hematuria). (2) The urinary Mφ of patients with active proliferative GN express FcgammaRIII (CD16) regardless of the type of GN. (3) There are two types of urinary CD68(+) cells, CD68(+)25F9(-) cells (infiltrating Mφ) and CD68(+)25F9(+) cells (mature Mφ). The CD68(+)25F9(-) cell counts in the urine correlate well with the activity of proliferative GN, and the CD68(+)25F9(+) cell counts in the urine correlate with the magnitude of non-selective proteinuria and with the subsequent decline of renal function. The CD68(+)25F9(+) cell count increases in the urine of patients with focal segmental glomerular sclerosis, but their numbers are negligible in minimal change nephrotic syndrome. These findings indicate that the analysis of the urinary Mφ phenotype is a useful strategy for evaluating renal injury as a 'risk-free renal biopsy'.

Immunosuppressive effect of deoxyspergualin in proliferative glomerulonephritis.

A clinical trial of the immunosuppressive drug deoxyspergualin (DSG) was conducted in five patients with various forms of proliferative glomerulonephritis (immunoglobulin A nephropathy in two patients, purpura nephritis in one patient, membranoproliferative glomerulonephritis in one patient, and rapidly progressive glomerulonephritis in one patient). DSG was intravenously administered at 0.25 or 0.5 mg/kg/d for 4 weeks. A marked decrease in proteinuria (to <50% of baseline) was observed in four patients, and the other patient showed a 38% reduction in proteinuria, but the proteinuria was exacerbated again after discontinuation of DSG in three patients during a 4-week follow-up period. Proinflammatory CD16(+) (FcgammaRIII) monocytes disappeared from the peripheral blood during the administration of DSG but reappeared after DSG treatment was discontinued. A significant decrease in urinary macrophage counts that was far more marked than the decrease in peripheral blood monocyte counts was observed after administration of DSG. Interestingly, we also observed that the CD16 marker on the CD14(+) macrophage population in the urine disappeared in response to DSG treatment. These findings suggest that DSG may have a unique effect of suppression of FcgammaRIII expression on monocytes and/or macrophages that may result in amelioration of activated macrophage-mediated glomerulonephritis.

Clinicopathological characteristics of interstitial foam cells in membranous nephropathy.

BACKGROUND: Interstitial foam cells are occasionally observed in various renal diseases, and they have been reported to belong to the monocyte/macrophage (M phi) lineage and to be associated with heavy proteinuria and hyperlipidemia. We investigated the characteristics of interstitial foam cells and their association with proteinuria and hyperlipidemia in idiopathic membranous nephropathy (MN). METHODS: Patients with MN (N = 320) were divided into two groups: group I consisted of 51 patients with interstitial foam cells, and group II consisted of the other 269 without foam cells. We compared clinical parameters and the findings of an immunohistochemical study using monoclonal antibodies to various types of leukocytes and adhesion molecules. RESULTS: The age at renal biopsy, the degree of proteinuria, serum levels of lipids, and other clinical parameters except for sex ratio were not different between the two groups. The ratio of nephrotic patients was compatible between groups I (56.9%) and II (52.8%). All interstitial foam cells were positive for CD68 and 25F9, which are markers for M phi and mature M phi, respectively, but were negative for CD3 or cytokeratin. Interstitial infiltrating cells were positive for CD68 and CD3 but were negative for 25F9. Furthermore, most of interstitial foam cells were positive for both leukocyte function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), but not for ICAM-3 (the third ligand for LFA-1). By contrast, most of infiltrating nonfoamy M phi s were positive for ICAM-3 and LFA-1, however, ICAM-1 was observed on only some of them. CONCLUSION: These results suggest that interstitial foam cells in MN may not depend on proteinuria nor hyperlipidemia directly. The accumulation of foam cells, which have characteristics of mature M phi, may be related to ICAM-1 as a ligand of LFA-1, whereas infiltration of nonfoamy M phi s has a close relationship with ICAM-3. Thus, the formation of interstitial foam cells may be related to the phenotypical transformation of M phi s.

Detection of urinary macrophages expressing the CD16 (Fc gamma RIII) molecule: a novel marker of acute inflammatory glomerular injury.

BACKGROUND: The CD16 antigen is the Fc gamma receptor III. CD14+CD16+ cells are proinflammatory monocytes/macrophages (Mo/M phi) that constitute a minor population in the peripheral blood of healthy individuals. Little is known about the expression of CD16 antigen on Mo/M phi in glomerulonephritis. METHODS: Flow cytometric analyses were performed on urine and blood samples obtained from 209 patients with various renal diseases. Patients variously suffered from rapidly progressive crescentic glomerulonephritis (RPGN), membranoproliferative glomerulonephritis (MPGN), postinfectious acute glomerulonephritis (AGN), Henoch-Schönlein purpura nephritis (HSPN), IgA nephropathy (IgAN), membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), lupus nephritis (LN), acute interstitial nephritis, hereditary nephropathy, idiopathic renal hematuria (IRH), and renal stone. RESULTS: The CD16+ M phi population of cells was present in the urine of hematuria-positive patients with proliferative glomerulonephritis, including AGN, IgAN, RPGN, MPGN, and LN with acute inflammatory lesions, such as endocapillary proliferation, tuft necrosis, and cellular crescents. In contrast, the urinary CD16+ M phi population was negligible in hematuria-positive patients with nonproliferative renal disease, including hereditary nephropathy, IRH, and renal stone and also in patients with proliferative glomerulonephritis lacking acute inflammatory lesions. Total urinary M phi of these patients were much less than those of patients having proliferative glomerulonephritis with acute inflammatory lesions. Transient expansion of the CD16+ M phi population in urine was observed during the acute exacerbation of urinary abnormalities, whereas the disappearance of CD16+ M phi closely preceded the amelioration of urinary abnormalities in patients with proliferative glomerulonephritis. In 38 of the 98 patients positive for CD16+ M phi population in urine, the CD16+ Mo population was negligible in peripheral blood. Immunohistochemically, CD16+ M phi were present in the glomeruli of active proliferative glomerulonephritis, whereas such cells were absent in inactive proliferative glomerulonephritis or nonproliferative glomerular diseases. CONCLUSION: CD16+ M phi may be effector cells involved in the acute inflammation common to all types of proliferative glomerulonephritis. Furthermore, the detection of CD16+ M phi in urine, as well as urinary M phi counts, may serve as a useful indicator of the active stage of proliferative glomerulonephritis.

Pathogenic role of glomerulo-tubular junction stenosis in glomerulocystic disease.

Glomerulocystic disease is an uncommon cystic renal condition characterized by cystic dilatation forming a glomerular cyst. The pathogenesis of this familial disease is unknown. We performed a serial section study using a biopsy specimen of a 16-year old female patient with glomerular cystic disease who had a family history of end stage renal failure. A total of 14 different glomeruli were analyzed, four of which exhibited a cystic appearance. Five glomerulotubular junctions were observed by serial sections, two of which had a stenotic appearance where glomerular cystic changes and periglomerular fibrosis were observed concomitantly. There were no such cystic glomerular changes in the other three glomeruli with non-stenotic glomerulo-tubular junctions. These findings suggest that the glomerular cystic lesion develops as a consequence of glomerulo-tubular junctional stenosis probably caused by periglomerular fibrosis.

[Effects of deoxyspergualin on proliferative glomerulonephritis].

A clinical trial of the immunosuppressive drug, deoxyspergualin (DSG), was conducted in five patients with various forms of proliferative glomerulonephritis (GN), such as IgA nephropathy in 2 patients, purpura nephritis in 1, membranoproliferative GN(MPGN) in 1, and rapidly progressive GN (RPGN) in 1 patient, respectively. DSG was intravenously administered at a daily dose of 0.25 or 0.5 mg/kg for 4 weeks. A marked decrease in proteinuria (to less than 50% of baseline) was observed in four patients. The other patient showed 38% reduction of proteinuria. However, proteinuria exacerbated again after discontinuation of DSG in three patients during a four-week follow-up period. Marked decrease (3,000/microliter) in white blood cell (WBC) counts was observed in three patients during the course of DSG treatment. We concluded that DSG therapy is beneficial in reducing proteinuria in patients with various forms of proliferative GN. However, since proteinuria increased after the discontinuation of DSG and serious leukocytopenia was observed, indiscriminate use of DSG in proliferative GN should be discouraged.

[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.

Clinicopathological significance of intratubular giant macrophages in progressive glomerulonephritis.

Very large macrophages, which we have termed "giant macrophages" (G-M phi), have been found in renal tubules, some containing cytoplasmic vacuoles. To elucidate their pathophysiological roles, we examined renal biopsy tissues from various primary glomerulonephritis (GN) and tubulointerstitial nephritis (TIN) using immunohistochemistry with monoclonal antibodies against M phi and other cell surface markers. Giant macrophages were absent or rare in TIN, minimal change nephrotic syndrome, and minor glomerular abnormalities, but G-M phi was plentiful in progressive glomerulonephrides such as IgA nephropathy with crescents, membranoproliferative GN, focal segmental glomerulosclerosis, and especially in crescentic GN. These G-M phi were usually seen in the lumen of renal tubules, but occasionally were found in the Bowman's spaces and glomerular tufts, and similar cells were also found in urine. Moreover, they frequently made contact with tubular epithelial cells expressing intercellular adhesion molecule-1, and the tubular epithelial cells in such lesions often had degenerative changes. Giant M phi may damage tubular epithelial cells from the luminal side. Phenotypically, G-M phi showed activated (CD71+) and mature (25F9+) characteristics along with features of M phi (CD68+), and the cytoplasm contained a great deal of lipids. The numbers of G-M phi in renal tissues closely correlated with the degree of hematuria (rho = 0.5, P < 0.001), serum creatinine value (r = 0.63, P < 0.001) in GN patients (N = 96) and with proteinuria in IgA nephropathy patients (r = 0.89, P < 0.001, N = 27). These data suggest that G-M phi are M phi that were activated and matured in certain active inflammatory sites, which flowed into tubules and then into urine. Thus, the existence of G-M phi in biopsy tissue or urine reflect the activity of GN and may have a predictive value for the progression of GN.

Detection of mature macrophages in urinary sediments: clinical significance in predicting progressive renal disease.

The ability to predict the rate of progression of renal parenchymal disease may help in its clinical management. We undertook characterization of urinary macrophages obtained from patients with various renal diseases paying special attention to the differentiation from non-progressive to progressive renal diseases. A total of 84 patients were divided into one of three categories. A highly progressive group included patients with rapidly progressive glomerulonephritis, diabetic nephropathy, membranoproliferative glomerulonephropathy, primary focal segmental sclerosis and diffuse proliferative lupus nephropathy, moderately progressive group included those with IgA nephropathy and Alport's syndrome and non-progressive group included patients with thin basement membrane nephropathy, minimal change nephrotic syndrome, idiopathic renal hematuria and urolithiasis. Urinary sediments were reacted with four monoclonal antibodies (CD68/macrophages vimentin, cytokeratin, and 25F9/mature macrophages). In normal individuals mature macrophages (25F9+ cells) were absent in urinary sediments. The number of 25F9+ cells in the urine was highest in the highly progressive group, less prominent in the moderately progressive group, and virtually absent in the non-progressive group. The 25F9+ cells reacted with anti-CD68 and antivimentin antibody, whereas the 25F9+ cells did not react with anti-cytokeratin antibody. These findings indicate that the detection of mature macrophages in urine is useful to estimate the prognosis of renal parenchymal diseases and may help to differentiate some glomerular diseases (e.g., thin basement membrane disease vs. Alport's syndrome, and minimal change nephrotic syndrome vs. primary focal segmental sclerosis).

Membranoproliferative glomerulonephritis in the aged and its possible causal relationship with CD8+CD57+ lymphocytes.

Membranoproliferative glomerulonephritis (MPGN) is a chronic progressive glomerulonephritis that occurs primarily in patients under the age of 30, and is rare in the elderly. We report eight aged patients with MPGN associated with CD8+CD57+ lymphocytosis. All eight patients showed a significant increase in CD8+CD57+ lymphocytes with a significant decrease in the ratio of CD4+ cells to CD8+ cells. Infiltration of CD8+CD57+ lymphocytes was observed within capillary lumens to various degrees according to the severity of endocapillary proliferation in each case. Expression of endothelial-leukocyte adhesion molecule-1 was observed in a focal and segmental manner on glomerular endothelial cells and on the endothelium of arterioles and arteries in kidney tissue in four cases in which a pronounced endocapillary proliferation was simultaneously seen. These findings suggest that cell-mediated cytotoxic mechanisms against glomerular endothelial cells may be involved in the pathogenesis of MPGN in the aged.

Familial lobular glomerulopathy: first case report in Asia.

A 23-year-old male Japanese student presented a unique lobular glomerulopathy characterized by mesangial and subendothelial expansion with numerous periodic acid-Schiff-positive deposits. Electron microscopy showed massive fine granular deposits with a homogeneous distribution. Fibrillar or microtubular structures were not demonstrated. Fibronectin was positive on immunostaining, as was immunoglobulin G and fibrinogen. Familial study revealed that the patient's grandfather, two aunts, and one cousin on his father's side had developed end-stage renal failure. Clinicopathologic features of this patient are identical with those of familial lobular glomerulopathy, which has been previously described by several investigators. Seven of the previously reported families were white and resided in the United States or in European countries. This is the first report of an Asian case, and indicates that this disease universally occurs independently of racial specificity.

Acoustic properties of dialysed kidney by scanning acoustic microscopy.

BACKGROUND: A correlation between acquired renal cysts in the dialysed kidney and renal cancer has long been debated, but no changes in the physical properties of kidneys at the microscopic level have been reported. The purpose of the present study was to classify the physical properties of the kidneys of patients undergoing haemodialysis at several stages of pathology by use of the scanning acoustic microscope. METHODS: Sixteen surgically excised kidneys of dialysis patients were investigated. Tissues were fixed in 10% formalin, frozen in acetone, and cut 10 microns thick on a cryostat. We used a scanning acoustic microscope operated in the frequency range of 100-200 MHz. Attenuation constant and sound speed were measured on a two-dimensional distribution. RESULTS: The attenuation constant for inflammatory granulation tissue was significantly higher than that for hyaline degeneration tissue (P < 0.001). Sound speed was high for granulation tissue, but tended to diminish gradually for hyaline degeneration. Sound speed increased again with progression to cystic degeneration (P < 0.001), but the attenuation constant remained low. When a cystic kidney contained a malignant lesion, the previously low attenuation constant rose at that site (P < 0.001), and the previously high sound speed was diminished (P < 0.001). CONCLUSION: Our data suggest that the physical properties of dialysed kidneys at different stages of pathology can be classified by their acoustic properties. Simultaneous evaluation of attenuation constant and sound speed is considered applicable to determining whether tissues contain malignant elements.