Cyclosporine protects glomeruli from FSGS factor via an increase in glomerular cAMP

Cyclosporine (CsA) administration to patients with recurrent focal segmental glomerulosclerosis (FSGS) after transplantation results in remission of proteinuria. We have shown that sera from patients with recurrent FSGS can increase the glomerular albumin permeability (Palbumin) and that increase in glomerular cAMP levels can alter the permeability characteristics of glomeruli in vitro. The purpose of this study was to determine if the increased glomerular levels of cAMP were related to the protective effects of CsA on an increase in Palbumin by FSGS sera. Glomeruli from Sprague-Dawley rats following intraperitoneal administration of CsA (25 mg/kg/day), cremophore (25 mg/kg/day), or saline for 5 days were incubated with 1:50 dilution of serum from three FSGS patients or with pooled normal human serum prior to calculation of Palbumin. Glomerular cAMP was measured by radioimmunoassay. Glomerular ultrastructural changes were assessed by transmission electron microscopy (TEM). Serum from three FSGS patients markedly increased Palbumin of glomeruli from saline or cremophore treated rats (saline, 0.68+/-0.08; 0.72+/-0.07; 0.70+/-0.07; and cremophore, 0.79+/-0.05; 0.81+/-0.02; 0.79+/-0.01; n=25 glomeruli in each group). In contrast Palbumin of glomeruli from CsA treated rats was not increased by any of the three FSGS sera tested (0.03+/-0.02; 0.04+/-0.05; 0.02+/-0.07, n=25 glomeruli in each group). Glomerular cAMP (pmol/mg of protein) increased 5 fold in CsA treated rats (328+/-26; 5 rats) compared with cremophore or saline treated rats (87+/-24 and 65+/-23, P<0.01; 5 rats in each group). The glomerular basement membrane appeared to be thickened and the lamina densa had an irregular appearance after treatment with CsA. No ultrastructural changes of glomerular epithelial or endothelial cells were evident. We conclude that CsA may have a direct protective effect on the glomerular filtration barrier in FSGS. We postulate that increased levels of glomerular cAMP by CsA may play an important role in protecting the glomerular Palbumin effect of the FSGS factor and may contribute to remission of proteinuria in FSGS patients.     

Age and ethnicity affect the risk and outcome of focal segmental glomerulosclerosis

In patients with proteinuria, African-American (AA) ethnicity is reported to be a risk factor for focal segmental glomerulosclereosis (FSGS) and its progression to end-stage renal disease (ESRD). We reviewed our single-center experience to determine the probability of FSGS and its progression to ESRD based on ethnicity and age at presentation in children with proteinuria with or without nephrotic syndrome. Proteinuria without systemic disease or acute glomerulonephritis was the presenting feature in 17% (236/1,403) of children in the renal patient database of Texas Children's Hospital, Baylor College of Medicine. Histopathological diagnoses were established in 107 of 236 patients (45%). FSGS was identified in 65 patients, accounting for 28% of all patients with proteinuria and 61% of patients who underwent renal biopsy. FSGS was more prevalent in AA (45%) than in non-AA patients (22%) (P=0.001), and AA patients with FSGS were older at presentation (12.7+/-4.4 years) than non-AA patients (5.6+/-4.6 years) (P<0.001). Among patients who underwent renal biopsy, increasing age at presentation increased the probability of having FSGS in AA but not non-AA patients (P=0.04). Five-year actuarial renal survival of FSGS was worse in AA (8%) than in non-AA patients (31%) (P=0.01). These data suggest an increased risk and worse outcome of FSGS in AA compared with non-AA children.     

Clinical and morphological predictors of renal outcome in adult patients with focal and segmental glomerulosclerosis (FSGS)

In this retrospective study, we examined 35 adult patients with biopsy-proven, primary focal and segmental glomerulosclerosis (FSGS) and nephrotic syndrome to determine whether any of the clinical and morphological features of FSGS were associated with a higher risk of a poor renal outcome. Clinical factors assessed were the age, sex, amount of urinary protein, and presence of microscopic hematuria, hypertension and renal dysfunction at onset in each patient. Morphological parameters included the number of segmental sclerosis and global sclerosis, sclerosis score, location of segmental sclerosis, mean glomerular diameter, grade of tubulo-interstitial changes, and presence of vascular lesions. Twenty-three patients (66%) were in complete or incomplete (partial) remission, and 12 (34%) were non-responders at the end of follow-up. On univariate analysis, the age at onset, sclerosis score, mean glomerular diameter, and grade of tubulo-interstitial changes in no response were significantly greater than those parameters in remission. Multivariate logistic regression analysis revealed that the degree of tubulo-interstitial changes and mean glomerular diameter were independent risk factors for a poor renal outcome. These findings suggest that the estimation of these latter two parameters allows the nephrologist to predict the probable course and prognosis of an adult with FSGS. Intensive and prolonged therapy is recommended for patients without these two morphological features.     

IgG subclass/IgM ratio and response to therapy in focal segmental glomerulonecrosis

Focal segmental glomerulosclerosis (FSGS) is relatively steroid resistant and no clinical or histological marker can predict the response to therapy. To investigate the role of serum immunoglobulin subclass/IgM in predicting the response to therapy in FSGS, serum concentrations of total IgG, IgG subclasses, and the ratio of serum IgG subclasses to total IgG (% IgG subclass) were measured in 27 children during the acute nephrotic state. Prednisolone, cyclophosphamide, and Persantine (dipyridamole) were given for 12 weeks. We divided the patients into good responders or poor responders according to clinical response. The clinical and nephrotic status were similar in both groups. Fourteen patients were good responders with higher serum IgGI/IgM than that of non-responders (4.00+/-0.67 vs. 1.61+/-0.20, P<0.05). There was no significant difference in IgG2/IgM between these two groups. These results suggest that higher serum IgGI/IgM ratios may be associated with a better clinical response. These changes may reflect dysregulation of immunoglobulin class switching in patients with FSGS.     

Plasma immunadsorption treatment in patients with primary focal and segmental glomerulosclerosis

BACKGROUND: In primary focal and segmental glomerulosclerosis (FSGS) renal prognosis is poor if no remission of proteinuria can be obtained by treatment. In some patients a permeability factor, responsible for damaging the glomerular epithelial cell and detectable by an in vitro test (GVV-test), seems to be present in the serum. METHOD: We determined the effects of an immunadsorption treatment (IAT) on proteinuria and glomerular permselectivity (using a neutral dextran and dextransulfate-sieving technique to assess glomerular size and charge selectivity) in five patients with FSGS in the native kidneys and three patients with recurrence of FSGS after kidney transplantation. Furthermore, we performed the GVV-test using sera obtained from the patients before and after therapy. RESULTS: IAT reduced proteinuria by more than 50% in four patients, all of whom had an improvement in glomerular-size selectivity. Charge selectivity was better preserved after therapy in three out of these four subjects. The GVV-test prior to IAT was positive in two patients who also responded clinically to therapy. After IAT the GVV-test was negative in all patients, indicating an elimination of the proteinuric factor in the two previously positive patients. CONCLUSION: We conclude that a positive GVV-test before treatment makes a favourable response of IAT on proteinuria likely in patients with FSGS. If a reduction of proteinuria can be obtained by IAT this is due to an improvement in glomerular size and/or charge selectivity.     

Monitored outpatient management of mild gestational hypertension remote from term in teenage pregnancies

OBJECTIVE: Our purpose was to compare maternal and perinatal outcomes of teenage and adult pregnancies with mild gestational hypertension remote from term managed with an outpatient program. STUDY DESIGN: A matched cohort design was used. Maternal and perinatal outcomes of 60 teenage pregnancies with mild gestational hypertension remote from term were compared with 120 adult controls 20 to 42 years old. The groups were matched for race, gestational age, and proteinuria status at enrollment. All were monitored on an outpatient basis with four times daily automated blood pressure measurement and daily assessment of weight, proteinuria, and fetal movement. RESULTS: The mean gestational age at enrollment was 33.5 +/- 2.6 weeks for both groups (range 27 to 36 weeks). Only 60% of teenagers had a high school degree or equivalent compared with 76% of adults (p = 0.024). The teenagers were more likely than the adults to be of single marital status (75% vs 13%, p = 0.015). The mean gestational age at delivery (37.0 +/- 2.0 vs 37.0 +/- 2.2 weeks), mean pregnancy prolongation (23.5 +/- 19.0 vs 24.5 +/- 17.4 days), and mean birth weights (2915 +/- 669 vs 2879 +/- 678 gm) were not statistically different between the teenagers and adults (all p > 0.05). There were no stillbirths, neonatal deaths, or cases of eclampsia in either group. CONCLUSIONS: In spite of a study population characterized by limited education, single marital status, and young age at enrollment, monitored outpatient management of mild gestational hypertension remote from term in teenage pregnancies is associated with maternal and perinatal outcomes similar to those observed in adults.     

Charge and size selectivity of proteinuria in children with idiopathic nephrotic syndrome

Experimental studies have pointed to charge selectivity as an important determinant of glomerular permeability to macromolecules. Loss of glomerular basement membrane (GBM) polyanion has been proposed as a cause of the selective proteinuria in minimal change nephrotic syndrome (MCNS). However, the presence of less-anionic albumin in urine than plasma from MCNS and focal and segmental glomerulosclerosis (FSGS) patients has been interpreted both as evidence for partial maintenance of charge selectivity and for involvement of other pathogenic mechanisms. The exact role of charge selectivity in the pathogenesis of nephrotic proteinuria remains controversial. We have examined the clearance of endogenous proteins of differing size and charge in children with idiopathic nephrotic syndrome (NS). Chromatofocusing was used to determine the isoelectric points (pIs) of albumins in paired plasma and urine samples from patients with FSGS (n = 6) and MCNS (n = 6). Charge selectivity was assessed by comparing the pIs of the fractions with the highest albumin concentration (model pI) in plasma and urine. The difference between the modal pIs was defined as the delta modal pI. Charge selectivity was also assessed from the albumin/transferrin and IgG4/IgG1 clearance ratios; size selectivity from the IgG1/albumin and IgG1/transferrin as well as the IgG4/albumin and IgG4/transferrin clearances. In children with FSGS, the mean (+/-SD) delta modal pI was -0.05 +/- 0.16, and in MCNS -0.05 +/- 0.11. Neither value differed significantly from zero. The albumin/transferrin clearance ratio showed no significant difference between FSGS and MCNS, but the IgG4/IgG1 clearance ratio was significantly higher in MCNS (P < 0.05). Size selectivity was significantly reduced in FSGS compared with MCNS (for IgG1/transferrin P < 0.01 and for IgG1/albumin P < 0.05). For IgG4/transferrin and IgG4/albumin, P was < 0.05. In conclusion, there was no evidence for residual charge selectivity in idiopathic NS associated with either MCNS or FSGS during nephrotic-range proteinuria. There was a significant loss of GBM size selectivity in children with FSGS with heavy proteinuria compared with children with MCNS with heavy proteinuria.     

Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients

BACKGROUND: Hepatitis C virus (HCV) infection has been described in association with various types of glomerular diseases, usually type I membranoproliferative glomerulonephritis and rarely membranous glomerulonephritis (MGN). In this article, we describe the first series of MGN exhibited in renal transplant patients and associated with HCV infection. METHODS: From January 1980 to December 1994, 2045 kidney transplantations were performed in our renal transplant units. A retrospective analysis demonstrated an overall 20% prevalence of HCV virus-positive patients; 409 transplanted patients were HCV positive (ELISA and RIBA). RESULTS: Fifteen patients developed an allograft MGN (3.66%) 24 months after renal transplantation. MGN appeared in the form of significant proteinuria (>1.5 g/24 h) with stable renal function. In all cases, graft biopsy demonstrated a thickening of the capillary wall, subepithelial electron-dense deposits, and IgG and C3 diffuse granular deposits along the basal membrane. Ten cases were considered de novo, two cases were considered recurrent MGN, and three cases were considered undetermined because the primary renal disease was chronic glomerulonephritis. All patients showed negative antinuclear antibodies and cryoglobulins, normal complement, and negative rheumatoid factors. During follow-up (an average of 2 years), 12 patients developed a progressive worsening of renal function, with increased serum creatinine and persistent proteinuria; 8 of the 12 patients returned to dialysis. Of the remaining three cases, two patients showed partial remission of nephrotic syndrome after high doses of steroids, and one patient persisted with stable renal function and proteinuria (<2 g/24 h.). CONCLUSIONS: In summary, HCV is preferentially associated with MGN in renal transplant patients, rather than with membranoproliferative glomerulonephritis as in the normal adult population. MGN associated with HCV infection has a similar clinical picture and outcome to posttransplant idiopathic de novo MGN, with persistent massive proteinuria and progressive deterioration of renal function.     

Preliminary description of focal segmental glomerulosclerosis in patients with renovascular disease

BACKGROUND: Primary and secondary forms of focal segmental glomerulosclerosis (FSGS) are common causes of glomerular proteinuria. Secondary forms of FSGS seem to be the result of adaptive changes that follow a reduction in renal mass. We saw an elderly patient with severe bilateral renal vascular disease (RVD) who had FSGS on percutaneous biopsy. To find out whether elderly patients with atherosclerotic RVD are predisposed to the development of FSGS, we reviewed all cases of FSGS at our institution between 1990 and 1995. METHODS: We identified 59 cases of biopsy-proven FSGS and examined clinical, histological, and radiographic records. FINDINGS: Of the 59 patients, 24 were older than 50 years; eight of these had RVD. No patient under the age of 50 had RVD. Seven of the eight patients with RVD and FSGS had substantial proteinuria at presentation. All had typical glomerular lesions with focal segmental tuft collapse and synechiae; other glomeruli were hypertrophic. All patients showed further decline in renal function on follow-up. INTERPRETATION: The association of FSGS and RVD may represent an under-recognised aetiology of significant proteinuria in elderly patients.     

Renal dopaminergic system in nephrotic syndrome and after remission

BACKGROUND: Although intrarenal dopamine is known to behave as an endogenous natriuretic hormone the role of the renal dopaminergic system in the sodium handling of nephrotic oedema remains unknown. STUDY DESIGN: We monitored the daily urinary excretion of free dopamine, L-DOPA-its precursor, and its metabolites, DOPAC and HVA, during sodium retention accompanying the nephrotic state and natriuresis leading to oedema mobilization in eight patients (mean age 8.0+/-2.4 years) with drug-induced remission of minimal-change nephrotic syndrome (MCNS). RESULTS: During natriuresis the urinary levels of dopamine did not increase in parallel with sodium excretion in any of the eight patients studied. Moreover, after remission of the nephrotic syndrome the urinary levels of dopamine were significantly lower than during the nephrotic state (1565.3+/-361.7 vs 2416.1+/-558.4, P= 0.02). In contrast, the urinary excretion of L-DOPA increased markedly during natriuresis resulting from remission of proteinuria (from 87.0+/-40.5 up to 296.9+/-86.3 nmol/24 h; P< 0.01). CONCLUSION: We conclude that the natriuretic response resulting from drug-induced remission of proteinuria in MCNS is accompanied by a decrease in the renal uptake/decarboxylation of L-DOPA to dopamine.     

Does advanced maternal age affect pregnancy outcome in women with mild hypertension remote from term?

OBJECTIVES: Our purpose was to compare maternal and perinatal outcomes of mature women with those in younger women with pregnancies complicated by mild hypertension remote from term. STUDY DESIGN: A matched cohort design was used. A total of 379 mature pregnant women (> or = 35 years old) with mild hypertension remote from term were matched for race, gestational age, and proteinuria status at enrollment with 379 adult controls aged 20 to 30 years also with mild hypertension remote from term. All were enrolled in an outpatient management program that included automated blood pressure measurements and daily assessment of weight, proteinuria, and fetal movement. RESULTS: The mean gestational age at enrollment was 32.7 +/- 3.0 weeks for both groups (range 24 to 36 weeks). By matching 20.6% of patients in each group had > or = 1+ proteinuria on urinary dipstick at enrollment, and 77.3% of patients in each group were white. Chronic hypertension was more common in the mature group (22.4% vs 14.5%, p = 0.007). The mean gestational age at delivery (37.2 +/- 2.3 vs 37.2 +/- 2.2 weeks), the mean pregnancy prolongation (28.1 +/- 21.0 vs 28.4 +/- 22.0 days), and the mean birth weights (2864 +/- 770 vs 2906 +/- 788 gm) were similar between the mature and younger groups (all p > 0.05). There were no differences regarding abruptio placentae (2 vs 3 cases) or thrombocytopenia or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome (7 vs 9 cases), and there were no cases of eclampsia. There were five stillbirths in the mature group and none in the younger group (p = 0.063). CONCLUSION: Outpatient management of mild hypertension remote from term in the mature pregnant women was associated with similar maternal outcomes but with a nonstatistically higher stillbirth rate compared with the younger pregnant woman.     

S100A1 regulates neurite organization, tubulin levels, and proliferation in PC12 cells

As a first step in determining what cellular processes are regulated by the calcium-modulated protein S100A1 isoform in neurons, the effects of ablated S100A1 expression on neurite organization and microtubule/tubulin levels in PC12 cells were examined. A mammalian expression vector containing the rat S100A1 cDNA in the antisense orientation with respect to a cytomegalovirus promoter was constructed and transfected into PC12 cells. Indirect immunofluorescence microscopy confirmed decreased S100A1 protein levels in all three stable transfectants (pAntisense clones) that expressed exogenous S100A1 antisense mRNA. In response to nerve growth factor, pAntisense clones extended significantly more neurites than control cells (4.01 +/- 0.16 versus 2.93 +/- 0.16 neurites/cell). This increase in neurite number was accompanied by an increase in total alpha-tubulin levels in untreated (4.0 +/- 0.6 versus 1.76 +/- 0.4 ng of alpha-tubulin/mg of total protein) and nerve growth factor-treated pAntisense clones (4.15 +/- 0.4 versus 2. 04 +/- 0.5 ng of alpha-tubulin/mg of total protein) when compared with control cells. At high cell densities, pAntisense clones exhibited a significant decrease in anchorage-dependent growth. In soft agar, pAntisense clones formed significantly more colonies (153 +/- 8%) than control cells (116 +/- 5%). However, the pAntisense soft agar colonies were significantly smaller than those observed in control cells (40.6 +/- 3.0 versus 59.5 +/- 1.2 micron). These data suggest that cell density inhibits both anchorage-independent and -dependent growth of pAntisense clones. In summary, ablation of S100A1 expression in PC12 cells results in increased tubulin levels, altered neurite organization, and decreased cell growth. Thus, S100A1 may directly link the cytoskeleton and calcium signal transduction pathways to cell proliferation.     

Transfection of C6 glioma cells with the bax gene and increased sensitivity to treatment with cytosine arabinoside

BACKGROUND: Prolonged dialysis is associated with acquired cystic kidney disease (ACKD) and also higher incidence of renal cell carcinoma. Relationship among dialysis, tubular cell proliferation, development of cystic change and neoplastic transformation is not clearly known. Whether dialysis causes additional stress on tubular cells is also conjectural. Study of heat shock protein (HSP) expression which are rapidly synthesized in cells in response to a variety of stresses may be helpful in this regard. METHODS: To evaluate dialysis induced early changes in end stage renal disease (ESRD), kidneys from eight adult autopsied patients were examined (group I) who were on weekly maintenance haemodialysis for 3-12 months. The heat shock protein (HSP 72/73) expression of tubular epithelial cells and their proliferating cell nuclear antigen (PCNA) labelling index (LI) were studied by immunohistochemistry using monoclonal antibodies. For comparison similar study was carried out in 10 cases of ESRD (Group II) of similar age and sex distribution who were not dialysed. The atrophic tubules were subtyped morphologically into (1) classic, (2) thyroid, (3) endocrine and (4) super tubules. RESULTS: In the dialysed group (I) the percentage of hyperplastic super tubules (10.6 +/- 4.1%) was significantly higher than in the non-dialysed group (II) (5.2 +/- 1.3%) with a higher PCNA LI (6.8 +/- 2.04%) (group II 4.9 +/- 1.9%) (P < 0.01 to < 0.001). Though grossly not detected, but microscopic cysts and microadenoma like areas were seen in all the cases in group I with a mean diameter of 522.66 +/- 315.25 microns and 494.85 +/- 262.46 microns respectively. They were seen in one case of group II. PCNA LI of the cells in microadenoma (7.2 +/- 3.1%) and microcysts (6.6 +/- 2.6%) were similar to that of super tubules in group I. Quantitation of HSP expression by image analysis (optical density 2.309 +/- 0.155) showed a positive correlation (r = 0.7555) (P < 0.001) with PCNA LI in super tubules indicating a higher induction in the dialysed group. CONCLUSIONS: This study suggests that haemodialysis may cause injury to tubular cells and aggravate stress on an already compromised situation of ESRD leading to increased cell proliferation and more hyperplastic supertubule formation which may be the forerunner of cyst formation as well as neoplastic transformation.     

Reactive plasmacytosis and lymphocytosis in acute myeloid leukemia

The association of plasmacytosis and lymphocytosis with acute myeloid leukemia (AML) has been documented in isolated case reports. We examined 149 cases (134 adults, 15 children) of newly diagnosed AML and found 9 adults (6%) with > or = 5% plasma cells and 1 child and 1 adult with > or = 20% lymphocytes. Lymphocytes constituted 25% and 42% of marrow cellularity in the adult and child respectively and persisted throughout remission in the child's marrow. The percentage of morphologically normal plasma cells ranged from 5% to 13% (mean 7%). Monoclonal immunoglobulins were not detected with immunostaining or flow cytometry. Hypergammaglobulinemia was present in 3 cases, and a monoclonal increase in IgG-kappa in 1. Plasmacytosis was not seen in remission marrows from these patients (n = 4). Lymphocytosis or plasmacytosis occurs in approximately 7% of patients with AML, appears reactive in nature, and may represent an immunological response to tumor. Monoclonal paraproteins may occur without other evidence of B-cell neoplasia.     

Long-term therapy of bronchial asthma with ingacort

To study the effectiveness of ACE-inhibitors in diabetic nephropathy (DN) 12 male and 16 female patients aged 13-21 years with DN having normal blood pressure (BP) were given ramipril (tritace) in a dose 2.5-5 mg/day in the course of 12-24 weeks. Efficacy and safety of the treatment were assessed by changes in albuminuria and proteinuria, BP. Reduction of albuminuria occurred in 19(79.1%) out of 24 patients with microalbuminuria, in 13(54.1%) of them urine excretion of albumin returned to normal levels. All the patients with proteinuria and macroalbuminuria benefited from ramipril therapy because their proteinuria diminished or even disappeared (2 cases). The persistence of the antiproteinuria effect on posttreatment week 12 was 66.6%. Ramipril effect on BP was minimal. It is inferred that ramipril is effective in the treatment of DN at the stage of microalbuminuria and proteinuria in patients with normal BP.     

Focal segmental glomerulosclerosis

Over the last 2 decades, we have learnt that focal segmental glomerulosclerosis (FSGS) is a ubiquitous phenomenon underlying the progressive deterioration of many different types of renal diseases in both pediatric and adult populations. FSGS may also be the primary renal lesion, whether in new disease entities such as glycogen storage disease and human immunodeficiency virus infection, or in idiopathic FSGS. Although the mechanism which triggers the development of primary FSGS still remains unknown, laboratory and clinical studies have identified several key pathophysiological events leading to end-stage renal disease. While therapeutic modalities have not changed remarkably, a recent study, although uncontrolled, demonstrated an impressive efficacy of intravenous steroid pulse therapy in inducing remission. Nevertheless, it remains largely unknown whether such a forced remission decreases the overall risk of developing chronic renal failure. Studies have revealed an important pathophysiological role of angiotensin and the therapeutic efficacy of angiotensin converting enzyme inhibitors in progressive loss of renal function in diseases where glomerulosclerosis is secondary; however, it remains to be verified whether these results hold true in primary FSGS. As a result of the improvement in allograft survival rate, the benefit of renal transplant outweighs the risk of recurrence of FSGS, hence transplantation continues to be a vital therapy for FSGS patients who have reached renal failure. Thus, FSGS is not one disease, but rather a range of lesions seen in many settings. The type of lesions and the patient's unique genetic factors contribute to prognosis, and also may dictate choice of optimum therapy.     

Elevated lipoprotein (a) levels in primary nephrotic syndrome

Elevated plasma levels of total cholesterol and increase in the hepatic synthesis of some apo B-containing lipoproteins have been noted in the nephrotic syndrome. Apoprotein (a), the apolipoprotein distinguishing lipoprotein (a) [Lp(a)] from low-density lipoprotein, is equally of hepatic origin, and Lp(a) recently has been shown to possess both atherogenic and thrombogenic activities. However, little is known of Lp(a) levels in nephrotic patients. We measured plasma Lp(a) concentrations in 11 patients with primary nephrotic syndrome in the absence of hematuria, hypertension, and renal insufficiency. Histologic lesions were minimal-change disease in five cases, membranous glomerulopathy in four cases, and focal and segmental glomerulosclerosis in two cases. Mean levels of Lp(a) (98 +/- 92 mg/dL [mean +/- SD]) were markedly elevated in the nephrotic patients as compared with the controls (14 +/- 13 mg/dL). No correlation was noted between plasma Lp(a) and proteinuria, albuminemia, total cholesterolemia, low-density lipoprotein cholesterol, apoprotein B100, or plasminogen. Furthermore, there was no correlation between Lp(a) levels and apoprotein (a) isoform size. In four patients, the level of Lp(a) decreased approximately fourfold after remission of the nephrotic syndrome under corticosteroid treatment. Our observation that Lp(a) levels are elevated in the nephrotic syndrome is consistent with the hypothesis that these patients may be at an increased risk of cardiovascular and thrombotic complications.     

Steroid therapy during the early stage of progressive IgA nephropathy. A 10-year follow-up study

This study was undertaken to clarify the effect of corticosteroids on the long-term clinical course of the early stage of progressive IgA nephropathy. The early stage of progressive IgA nephropathy was defined as having moderate proteinuria between 1 and 2 g/day, creatinine clearance values of 70 ml/min or more, and a histological severity score of 7 or more. The number of patients who fulfilled these three conditions during 12 years from 1972 and then were continuously followed up for 10 years or more in our renal unit was 46. Twenty of them received steroid treatment for an average period of 18 months, and the remaining 26 patients had no steroid treatment. The initial data of proteinuria, creatinine clearance values, frequency of hypertensive cases, and histological scores of 7 or more were not different between the two groups: 1.4 +/- 0.4 vs. 1.3 +/- 0.3 g/day, 85 +/- 14 vs. 88 +/- 13 ml/min, 25 vs. 38%, and 10.7 +/- 2.5 vs. 11.0 +/- 3.0, respectively. During the follow-up period of 10 years, the renal survival rate was significantly different between the two groups (100 vs. 84% 5 years after starting therapy and 80 vs. 34% 10 years later; p < 0.001). The final creatinine clearance values were significantly different between the two groups (54 +/- 35 vs. 20 +/- 29 ml/min; p < 0.005). On the other hand, the patient groups with mild histological changes or decreased renal function due to moderate proteinuria showed no significant differences in the final outcome. These results indicate that corticosteroids are beneficial in stabilizing the renal function for a long time during the early stage of progressive IgA nephropathy, although this study was not a randomized one.     

Transplantation of autologous peripheral blood progenitor cells procured after high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia in first remission

The purpose of the study was to evaluate the feasibility and efficacy of high-dose cytarabine-anthracycline consolidation chemotherapy followed by autologous transplantation of chemotherapy/rHuG-CSF-mobilized peripheral blood progenitor cells for adult patients with acute myelogenous leukemia in first remission. Fifty-nine consecutive patients (median age 45, range 18-69) with acute myelogenous leukemia in first remission were enrolled on a study of high-dose cytarabine-mitoxantrone consolidation chemotherapy used as a method of in vivo purging for the purpose of autologous peripheral blood progenitor cell transplantation. A median of 7 x 10(8) peripheral blood mononuclear cells/kg were infused 1 day after preparative conditioning with 11.25 Gy total body irradiation and cyclophosphamide (120 mg/kg). Forty-six patients received myeloablative chemo-radiotherapy followed by the infusion of chemotherapy/rHu-G-CSF-mobilized autologous peripheral blood progenitor cells. The median time to both neutrophil and platelet recovery from transplant was 15 days (range, 11-36 and 5-253+ days, respectively). After a median follow-up of 27 months, 31 patients remain alive with 27 in complete remission. Median remission duration for all eligible patients is 12 months, and actuarial leukemia-free survival at 3 years is 42 +/- 14%. The actuarial risk of relapse is 54 +/- 15%. Toxicity of autologous peripheral blood progenitor cell transplant included treatment-related death in two patients and grade III/IV organ toxicity in six. Advanced age was a negative prognostic factor for leukemia-free survival. Our results demonstrate that autologous transplantation of chemotherapy-mobilized peripheral blood progenitor cells is feasible in an unselected population of adult patients with acute myelogenous leukemia in first remission producing improved leukemia-free survival with minimal toxicity.     

Intraarticular corticosteroid injection in the management of children with chronic arthritis

OBJECTIVE: Intraarticular (IA) corticosteroid injection is a common therapeutic approach in the management of adult rheumatoid arthritis. This study examined the safety and efficacy of IA corticosteroid injection in 71 patients with juvenile arthritis who were being seen at the Sheba Medical Center during the years 1991-1996. METHODS: Sixty-one patients fulfilled the American College of Rheumatology revised criteria for the diagnosis of juvenile rheumatoid arthritis (JRA), 6 patients had reactive arthritis, and 4 patients had various other arthritic conditions. The mean +/- SD age was 9.4 +/- 5.6 years (range 0.5-18 years); 47 were female (mean age 8.1 +/- 5.5 years) and 24 were male (mean age 10.8 +/- 5.4 years). A total of 300 joints were injected with triamcinolone hexacetonide. The most common sites of injection were the knees (124 injections), ankles (71 injections), wrists (46 injections), shoulders (10 injections), and elbows (7 injections). Children under the age of 6 (n = 17), or older children who received more than 4 joint injections at one time (n = 10) were sedated with either ketamine HCI or propofol. All other children received their joint injections under local anesthesia. RESULTS: Full remission of the joint inflammation lasting >6 months following injection was achieved in 246 of the 300 injections (82.0%). In 54 (18.0%) of the injected joints, the inflammation recurred within 6 months of injection. In patients with pauciarticular arthritis, 115 of 141 injections (81.6%) resulted in full remission. Discontinuation of all oral medications was accomplished in 43 patients (60.6%) of the total group of 71 patients and in 32 of the 43 patients with pauciarticular disease (74.4%). Correction of joint contraction was achieved in 42 children (55 joints). In all 11 patients with Baker's cyst and in 12 patients with tenosynovitis, complete remission was achieved following injection. No infection or other serious complications occurred in any of the patients following the procedure. CONCLUSION: IA corticosteroid joint injection in children with juvenile arthritis is a safe and effective mode of therapy. It may be the only therapy needed in patients with pauciarticular JRA, obviating the need for prolonged oral medications, and is effective in correcting joint contractions and deformities.