World Health Organization Class Research Articles

Effects of the oral endothelin-receptorantagonist bosentan on echocardiographicand doppler measures in patients with pulmonary arterial hypertension

ObjectivesThe purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) on echocardiographic and Doppler variables in 85 patients with World Health Organization class III or IV pulmonary arterial hypertension (PAH). BackgroundBosentan, an orally active dual endothelin-receptor antagonist, improves symptoms, exercise capacity, and hemodynamics in patients with PAH. MethodsPatients had primary pulmonary hypertension (84%) or PAH associated with connective tissue disease. Of these, 29 patients received placebo and 56 received bosentan (1:2 randomization). Six-minute walk tests and echocardiograms were performed at baseline and after 16 weeks of treatment. ResultsBaseline characteristics were similar in the placebo and bosentan groups, and echocardiographic and Doppler findings were consistent with marked abnormalities of right ventricular (RV) and left ventricular (LV) structure and function that were due to PAH. The treatment effect on 6-min walking distance was 37 m in favor of bosentan (p = 0.036). Treatment effects of bosentan compared with placebo on other parameters were as follows: Doppler-derived cardiac index = +0.4 l/min/m2(p = 0.007), LV early diastolic filling velocity = +10.5 cm/s (p = 0.003), LV end-diastolic area = +4.2 cm2(p = 0.003), LV systolic eccentricity index = −0.12 (p = 0.047), RV end-systolic area = −2.3 cm2(p = 0.057), RV:LV diastolic areas ratio = −0.64 (p = 0.007), Doppler RV index = −0.06 (p = 0.03), and percentage of patients with an improvement in pericardial effusion score = 17% (p = 0.05). ConclusionsBosentan improves RV systolic function and LV early diastolic filling and leads to a decrease in RV dilation and an increase in LV size in patients with PAH.

Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS.

Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.

Bosentan.

Bosentan is the first endothelin (ET) receptor antagonist approved by the Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). In patients with World Health Organization Class III and IV PAH, bosentan has demonstrated improvement in dyspnea and exercise tolerance. ET also plays an important role in the pathophysiology of different vascular diseases. Therefore, bosentan also may have the potential to alter the outcome of many other diseases, such as heart failure, hypertension, ischemic heart disease, and renal disease, as well as cerebrovascular disorders. Because of the rarity and the poor prognosis of patients with PAH, as well as the requirement of close monitoring of bosentan (due to its potential of causing liver dysfunction and its teratogenic effects), bosentan is currently available only through a special access program and is distributed by certain selected pharmacies. Patients who are receiving bosentan should be taught to recognize early signs and symptoms of liver dysfunction and possible pregnancy. In addition, bosentan is not only a substrate but also an inducer of CYP3A4 and CYP2C9. Therefore, it is anticipated that numerous drug interactions may occur. Patients should be advised to consult their physicians or pharmacists should they need to consume other prescription or nonprescription medications.

Identification of IgG subclasses and C-reactive protein in lupus nephritis: the relationship between the composition of immune deposits and FCgamma receptor type IIA alleles.

To characterize the subclass composition of IgG deposited in lupus glomeruli, to examine its relationship to allelic polymorphisms of IgG receptors (Fcgamma receptors [FcgammaR]), and to determine whether C-reactive protein (CRP), a ligand for FcgammaRIIa, is present in these immune deposits. Renal biopsy samples from 80 patients with lupus nephritis were examined by light microscopy and indirect immunofluorescence with IgG-subclass-specific monoclonal antibodies. FcgammaRIIA genotypes were determined using allele-specific polymerase chain reaction. Immunostaining for CRP was performed on lupus and nonlupus glomerulonephritis specimens. IgG2 and IgG3 were the predominant subclasses in immune deposits in all World Health Organization classes of nephritis. The frequency of genotypes containing the low-binding IgG2 allele, FcgammaRIIa-R131, was significantly greater than expected in patients with class III or class IV nephritis and in patients with intense IgG2 deposition. CRP, a ligand with particular affinity for FcgammaRIIa-R131, was consistently present in the renal immune deposits of lupus nephritis specimens. FcgammaRIIA genes are associated with proliferative renal disease and may contribute to disease pathogenesis. FcgammaRIIa-R131, the variant with low affinity for IgG2, has high affinity for CRP. Thus, FcgammaRIIa-R131 may contribute to impaired removal of circulating immune complexes, as well as efficiently triggering phagocyte activation and the release of inflammatory mediators within glomeruli.

New approach to polycystic ovary syndrome and other forms of anovulatory infertility.

Anovulation can be classified in the clinic on the basis of serum hormone assays. Low gonadotropins along with low estrogen concentrations are suggestive of a central origin of the disease, whereas low estrogen levels along with elevated gonadotropins indicate a primary defect at the ovarian level. Most anovulatory patients (approximately 80%) present with serum FSH and estradiol levels within the normal range (World Health Organization class II). Polycystic ovary syndrome (PCOS) is a common but poorly defined heterogeneous clinical entity. Historically, characteristic ovarian abnormalities represented a hallmark of the syndrome. Because several etiological factors may lead to a similar end point (i.e., polycystic ovaries), the development of a clinically applicable classification of the syndrome has proven difficult. Clinical, morphological, biochemical, endocrine, and, more recently, molecular studies have identified an array of underlying abnormalities and added to the confusion concerning the pathophysiology of the disease. Despite the vast literature regarding the etiology and classification of PCOS, no consensus has been reached regarding the validity of criteria used to diagnose the syndrome. For instance, the significance of elevated serum luteinizing hormone (LH) concentrations, insulin resistance or polycystic-appearing ovaries assessed by ultrasound for PCOS diagnosis remains uncertain. In contrast, hyperandrogenism and chronic anovulation generally are believed to be mandatory diagnostic features. Patients with PCOS might visit a dermatologist for hirsutism, a generalist, or internist for complaints related to obesity or a gynecologist for irregular or absent bleeding. However, most patients seek the care of a gynecologist because of cycle abnormalities (oligomenorrhea) and infertility. In PCOS, serum FSH and estradiol (E2) levels are usually found to be within the (broad) normal ranges, whereas LH may either be normal or elevated. Because PCOS with normal or high LH does not seem to represent different clinical entities, it seems justifiable to consider this syndrome as a subgroup of WHO-II patients, although estrogen levels may be tonically elevated in these patients. This review will focus on characteristics of the heterogeneous group of WHO-II patients in an attempt to identify factors involved in the etiology and possible ovulation induction outcome of PCOS. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader will be able to outline the current classification of anovulatory infertility and to explain the characteristics and features used for classification.

Retrospective analysis of outcome in a cohort of patients with lupus nephritis treated between 1977 and 1999.

To review the development, histological type and outcome of a cohort of patients with lupus nephritis who were managed and followed up by the specialist Bloomsbury Rheumatology Unit between 1977 and 1999. Seventy-eight of the 280 (28%) patients with systemic lupus erythematosus (SLE) developed nephritis. Occurrence of end stage renal disease (ESRD) according to World Health Organization (WHO) class was analysed, and patients were subdivided according to whether treatment included at least six pulses of intravenous (i.v.) cyclophosphamide (CYC) once a month. For patients with WHO class III nephritis, three out of five treated with i.v. CYC developed ESRD compared with none out of 10 not treated with i.v. CYC (P < 0.02). There was no significant difference between these subgroups in terms of a variety of parameters with good prognostic value, except anti-dsDNA titre at time of biopsy (which was greater in the former). For patients with WHO class IV nephritis, three out of 16 treated with i.v. CYC developed ESRD, compared with five out of 20 not treated with i.v. CYC (no significant difference). These data suggest that there may be a subgroup of patients with lupus nephritis (WHO class III) whose long-term outcome is not adversely affected by the omission of i.v. CYC.

A novel interleukin-8 polymorphism is associated with severe systemic lupus erythematosus nephritis

Interleukin-8 (IL-8) is a potent neutrophil chemokine that has been implicated in the pathogenesis of renal inflammation in human glomerulonephritis. To explain inter-patient variations in renal inflammation during diseases such as systemic lupus erythematosus (SLE), it was postulated that the promoter region of the IL-8 gene contains polymorphic residues that influence the level of IL-8 expression in response to immune-complex deposition, and thereby affect the severity of renal injury. This study was undertaken to identify polymorphisms in the 5'-flanking region of the IL-8 gene that correlate with the severity of SLE nephritis. A 1526 base pair segment of the IL-8 5'-flanking region was PCR amplified from the genomic DNA of 100 individuals and sequenced on an automated capillary electrophoresis system. Sequence data were compared with the published IL-8 sequence to identify polymorphisms. Allelic variations were verified by cloning and re-sequencing, and also by restriction enzyme analysis. Patients with SLE nephritis were genotyped for IL-8 polymorphisms, and associations between specific alleles and severity of SLE nephritis [based on the World Health Organization (WHO) classification] were determined. Three single nucleotide polymorphisms were identified in the IL-8 flanking region. Labeled relative to the IL-8 translational start site, these are T-845C, T-738A, and A-353T. T-845C and T-738A are novel, and found primarily in African Americans. The C for T change at position -845 was found to be 3.6 to 7.5 times more frequent in African Americans with severe (WHO Class IV) SLE nephritis, than in African American controls, or patients with less severe forms of SLE nephritis, respectively. IL-8-845C might predispose African Americans with SLE nephritis to more severe renal injury, perhaps by influencing IL-8 expression. Genotyping patients with glomerulonephritis for IL-8 polymorphisms may be useful in predicting disease outcome and individualizing immunosuppressive therapy.

Urine Macrophage Migration Inhibitory Factor Reflects the Severity of Renal Injury in Human Glomerulonephritis

ABSTRACT. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in experimental crescentic glomerulonephritis (GN). Renal expression of MIF is also upregulated in human GN and correlates with leukocytic infiltration, histologic damage, and renal dysfunction. The study presented here examined whether MIF can be measured in urine and if so, whether the urine MIF concentration reflects the degree of renal injury. Urine and serum MIF was measured by enzyme-linked immunosorbent assay in 10 normal healthy volunteers and in a cohort of 63 patients with GN (2 thin basement membrane disease [TBM], 15 membranous GN, 10 focal segmental glomerular sclerosis, 20 IgA glomerularnephritis, 11 crescentic GN, 10 systemic lupus erythematosis World Health Organization class IV). Renal MIF expression was assessed by immunostaining of biopsy tissue. MIF was detected in urine from normal volunteers (mean ± SD; 191 ± 132 pg MIF/μmol creatinine). The urine MIF concentration was unchanged in patients with nonproliferative nephropathies (343 ± 397 pg MIF/μmol Cr) but was increased 3.4-fold in proliferative nephropathies (645 ± 527 pg MIF/μmol Cr; P &lt; 0.05 versus normal and nonproliferative). Stratified analysis showed the greatest increase in urine MIF in crescentic GN (4.5-fold). In contrast, serum MIF levels were not different between normal patients and any patient group. Immunostaining demonstrated a significant increase in renal MIF expression in proliferative glomerulonephritides that was associated with macrophage and T cell infiltration. There was a significant correlation between the urine MIF concentration and renal MIF expression, but not with serum MIF, indicating a renal origin for the excreted urine MIF. The urine MIF concentration also correlated with the degree of renal dysfunction, histologic damage, and leukocytic infiltration, but not with the amount of proteinuria. In conclusion, this study shows that the urine MIF concentration is significantly increased in proliferative forms of GN and correlates with the degree of renal injury. Urine MIF levels reflect MIF expression within the kidney and may be a useful noninvasive tool for monitoring patients with crescentic GN, particularly in disease exacerbation.

Treatment of diffuse proliferative lupus glomerulonephritis: A comparison of two cyclophosphamide-containing regimens

Cyclophosphamide (CYC) has proven beneficial in preserving renal function in patients with lupus with diffuse proliferative glomerulonephritis (DPGN). However, the optimal route of CYC administration is unknown because direct comparative studies are unavailable. In this open study, we compared the renal outcome of two historical cohorts of patients with diffuse proliferative lupus nephritis (World Health Organization classes IVa and IVb) treated with either intravenous (IV) pulse CYC (group A; n [equals] 22) or sequential oral CYC followed by azathioprine (AZA; group B; n [equals] 21) and followed up prospectively. Both groups of patients had similar clinical, biochemical, and renal parameters at baseline. At 24 months posttreatment, significant improvements in proteinuria, creatinine clearance, serum albumin level, and lupus serological results were evident in both groups. Compared with patients in group A, patients in group B had more complete or partial remission (90% versus 73%) and less risk for treatment failure (5% versus 14%), renal flares (5% versus 14%), and doubling of creatinine levels (5% versus 9%), but the difference was not statistically significant. However, patients treated with oral immunosuppression had an insignificant increase in rates of herpes zoster infection (19% versus 9%) and menstrual disturbance (50% versus 29%). We conclude that sequential oral immunosuppression with CYC and AZA tended to have better efficacy than IV pulse CYC in the treatment of lupus DPGN but was associated with more toxicities. Additional randomized trials involving a larger cohort of patients with a longer period of observation are necessary. [copy ] 2001 by the National Kidney Foundation, Inc.

Alveolar hemorrhage and renal microangiopathy in systemic lupus erythematosus.

Acute alveolar hemorrhage in systemic lupus erythematosus usually occurs as a pulmonary-renal syndrome. In most cases, the lungs show "bland" alveolar hemorrhage with little or no inflammation. Whether this alveolar injury is similar to the better-defined noninflammatory renal lupus vasculopathy is unresolved. To investigate the relationships and the mechanisms of small vascular injury in the lung and kidney of 2 lupus patients who died of diffuse AH. We investigated the relationship of AH to immune complex deposition in the lungs of 6 patients with systemic lupus erythematosus and correlated the findings with glomerular and vascular disease in the kidney. Lung and kidney were studied by light, immunofluorescence, and/or electron microscopy; apoptosis was investigated using in situ nick-end labeling. The clinical course of 2 patients was complicated by alveolar hemorrhage, and the lungs of these patients revealed alveolar wall immune complex deposits and bland alveolar hemorrhage. These 2 patients had World Health Organization class IV lupus nephritis and renal arterioles involved by a noninflammatory lupus vasculopathy. Apoptosis was identified in the lupus microangiopathy and in alveolar walls within areas of alveolar hemorrhage. Alveolar wall immune complex deposits were not found in 4 patients who had a lupus glomerulonephritis but did not have renal lupus vasculopathy. Apoptosis was not seen in renal arterioles or lungs of these 4 cases, except in areas of diffuse alveolar damage or herpesvirus pneumonia. Our findings indicate that alveolar hemorrhage in systemic lupus erythematosus, characterized by bland alveolar wall changes, is pathogenetically similar to the lupus microangiopathy of the kidney. In both lung and kidney, the pathogenesis of the microvascular injury appears to be related to immune complex deposition and the induction of apoptosis.

Lupus nephritis in a child with AIDS

Concomitant acquired immunodeficiency syndrome (AIDS) and lupus nephritis is an exceptional feature in white patients. A white boy with maternofetal human immunodeficiency virus (HIV) infection had no medical follow-up until he presented at 12 years of age with a nephrotic syndrome, macrohematuria, renal failure, pancytopenia, and low CD4(+) cell count. A renal biopsy revealed severe lupus nephritis (World Health Organization class IV) with specific immune deposits in the absence of any clinical sign of systemic lupus erythematosus or specific autoantibodies at the time of diagnosis. The treatment consisted of methylprednisolone pulses followed by oral prednisone; antiretroviral triple therapy was started a few weeks later, which contributed to clinical and biologic improvement. To our knowledge, this is the first case report of lupus-like nephritis in a white child with AIDS, whose outcome might be improved significantly by a combination of steroids and antiretroviral therapy.

Predominance of Th1 immune response in diffuse proliferative lupus nephritis.

Lupus nephritis, which shows various histologic patterns, is a serious complication of systemic lupus erythematosus (SLE). We previously demonstrated the importance of Thl cell-mediated immune response in patients with diffuse proliferative lupus nephritis (DPLN). The aim of this study was to examine the relationship between the peripheral blood Th1/Th2 balance and the intrarenal immune response. The Th1:Th2 ratio in peripheral blood was measured by intracellular staining for cytokines with flow cytometry. Immunohistochemical analysis of renal biopsy specimens was performed to clarify the characterization of local infiltrating cells in 3 groups of subjects: SLE patients with World Health Organization (WHO) class IV nephritis (DPLN) (group I; n = 13), SLE patients with WHO class V nephritis (group II; n = 9), and patients with minor glomerular lesions (group III; n = 7). In addition, the histologic activity index and chronicity index were evaluated and correlated with the Th1:Th2 ratio. Immunohistochemical studies showed higher numbers of CD68+ macrophages, CD3 + T cells, and interferon-gamma-positive cells in group I than in groups II or III. Renal tissues from patients in group I also showed up-regulation of expression of osteopontin and CD40, with a small number of infiltrating T cells expressing interleukin-4. Overall, the Thl:Th2 ratio in group I patients (SLE with DPLN) was high and correlated significantly with the histologic activity index, but not with the chronicity index. We have identified a predominance of Thl-type response in both peripheral and renal tissues of patients with DPLN, suggesting that the peripheral blood Thl:Th2 ratio directly reflects the local histopathologic findings. In patients with lupus nephritis, the peripheral blood Th1:Th2 ratio could be useful as a parameter that reflects the renal histologic activity or the strength of the local Thl response.

Predictors of renal outcome in diffuse proliferative lupus nephropathy: data from repeat renal biopsy.

Diffuse proliferative lupus nephropathy (DPLN) is the most frequent and severe form of renal disease in patients with systemic lupus erythaematosus. Histological parameters at the initial biopsy of patients with DPLN that would predict the progression of renal pathology or function at the second biopsy are not clearly defined. The prognostic significance of renal histological indices, such as glomerular activity index and volume density of cortical interstitium [Vv(int/cortex)], was evaluated from successive renal biopsies in 21 patients with DPLN. At the time of the second biopsies, performed an average of 43 months after the first biopsies, seven patients (33%) showed progressive renal insufficiency. Only three cases (14%) transformed to World Health Organization class I or III. The seven patients with clinical progression exhibited a higher frequency of hypertension, higher percent glomerulosclerosis, and larger Vv(int/cortex) at the time of second biopsy as compared with the 14 patients without renal insufficiency. At the first biopsy, patients with clinical progression showed a higher glomerular activity index (2.9+/-1.2 vs 1.3+/-0.8, P<0.05) and larger Vv(int/cortex) (0.13+/-0.07 microm(3)/microm(3) vs 0.05+/-0.03 microm(3)/microm(3), P<0.05) than the patients without progression. The glomerular activity index at the first biopsy correlated directly with per cent glomerulosclerosis, Vv(int/cortex), and serum creatinine level at the second biopsy. Vv(int/cortex) in the first biopsy also showed a significant relation with per cent glomerulosclerosis and serum creatinine level at the second biopsy. These results suggest that higher glomerular activity and larger interstitial volume density at the initial biopsy can predict future progression of renal pathology or function in DPLN.

Transplantation and 2-year follow-up of kidneys procured from a cadaver donor with a history of lupus nephritis.

Two patients underwent cadaver transplantation with kidneys from a donor with a history of World Health Organization Class IV/V lupus nephritis, and we report their clinical and pathological outcome. The donor had a diagnosis of lupus nephritis made by renal biopsy 5 years before donation. At the time of donation, a biopsy was performed on the donor and on one of the recipients at 2 months and 1 year after the transplant. Both recipients underwent uneventful renal transplantation. On the first postoperative day, the donor's final pathological results became available. Although the frozen section seemed to be quite benign, the permanent sections revealed World Health Organization Class II/V lupus nephritis, with full house immunofluorescence and multiple electron dense deposits. Biopsies were performed on recipient #2 at 8 weeks and 1 year after the transplant. These revealed marked diminution followed by complete resolution of all tubular reticular structures and deposits as well as immunofluorescent activity. Both recipients remain with normal renal function and urinalysis at 3 years after the transplant. Although a history of clinically significant renal disease has been considered an absolute contraindication to kidney donation, with appropriate workup and caution, select patients may still be considered, which would increase the potential donor pool.

The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations.

To determine the clinical spectrum of disease in humans with mutations in the CD95 (Fas/ APO-1) receptor and to obtain mechanistic insight into the different clinical phenotypes observed. Clinical information for each of the index cases, first-degree relatives, and any family members reported to have Canale-Smith syndrome (or another autoimmune disease) was gathered by direct interview, chart review, and verification of data by the physician or pathologist concerned. Apoptosis of activated T or B lymphocytes was induced by agonistic anti-CD95 antibodies and quantified by a cell death assay (propidium iodide staining in the subdiploid peak) or cell viability assay (alamar blue or 3H-thymidine incorporation). Evaluation of an additional 8 probands with novel heterozygous CD95 mutations revealed hypergammaglobulinemia and immune-mediated cytopenias in all patients, as well as urticarial rash, oral ulceration, lymphopenia, and peripheral neuropathy in some individuals. One patient (P4) had systemic lupus erythematosus (SLE) characterized by a World Health Organization class V lupus nephropathy, a recurrent, reversible multifocal central nervous system disorder, high-titer antiphospholipid autoantibodies, and autoimmune cytopenias. In the P4 pedigree, the father had reduced T and B cell apoptosis associated with a CD95 mutation, whereas an independent B cell apoptotic defect was demonstrated in maternal family members who did not have a CD95 mutation. Three cases of B cell lymphoma occurred in carriers of the CD95 mutation. CD95 mutations are associated with loss of regulation of B lymphocytes, which predisposes to systemic autoimmunity including SLE. The P4 family provides a model of the complex genetic and functional interactions that are required for the development of a lupus-like syndrome.

Lupus nephritis in Southern Chinese patients: clinicopathologic findings and long-term outcome.

Despite the improvement in survival of patients with systemic lupus erythematosus (SLE) and associated nephritis in the past 20 years, few studies of the long-term outcome of large cohorts of patients with well-defined histological classes of lupus nephropathy are available. We examined the long-term outcome of 183 patients with lupus nephritis (LN) followed up by the Division of Rheumatology at Queen Mary Hospital (Hong Kong) between 1976 and 1997. Their renal biopsies were classified according to World Health Organization (WHO) criteria. There were 27 men and 156 women. Initial renal biopsy showed the following WHO classes of LN: 2 patients (1%), class I; 9 patients (5%), class II; 46 patients (25%), class III; 101 patients (55%), class IV; and 25 patients (14%), class V. The mean duration of follow-up from the renal biopsy was 130.7 +/- 5.9 months (range, 13 to 260 months). The overall 5-, 10-, and 15-year survival and renal survival (survival without dialysis) rates were 98.9%, 94.4%, and 94.4% and 92.1%, 81.2%, and 75.2%, respectively. Univariate analysis showed class IV nephritis, hypertension, impaired renal function (glomerular filtration rate < 50 mL/min), nephrotic syndrome at time of renal biopsy, and failure of complete remission in the first year of treatment were unfavorable predictors for renal survival. Multivariate analysis using the Cox regression model also showed persistent hypertension, class IV nephritis, and incomplete renal remission in the first year were independent risk factors for renal failure. Our results showed the renal survival rate of our patients from South China with LN was similar to that of most reported series of white patients. Prospective randomized studies with well-defined treatment protocols are needed to delineate the optimal treatment strategy for LN.

Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus.

To analyze the Th1/Th2 balance of peripheral Th cells in patients with systemic lupus erythematosus (SLE). The Th1:Th2 ratio was analyzed in 3 groups: SLE without proteinuria (group I; n = 23), SLE with proteinuria (group II; n = 31), and normal controls (group III; n = 24). Group II patients who had undergone renal biopsy were classified into 3 subgroups based on their renal histopathologic findings. The intracellular cytokine detection method with flow cytometry was used to quantitate Th1 and Th2 cells. There was no difference in the mean Th1:Th2 ratio between SLE patients (groups I and II) and healthy controls (group III). However, the mean value in group II was significantly higher than those in groups I and III. Moreover, within group II, the mean value in SLE patients who had diffuse proliferative lupus nephritis (World Health Organization class IV) was especially high. Although SLE has been considered to be a disease in which Th2 cells predominate, the Th1/Th2 balance of peripheral Th cells in SLE patients in the present study did not show a predominance of these cells. In contrast, among SLE patients with WHO class IV lupus nephritis, there was a strong predominance of Th1.

Spatial arrangement of subepithelial deposits in lupus and nonlupus membranous nephropathy.

Subepithelial deposits are a common feature of idiopathic membranous glomerulonephritis (MGN) and lupus membranous glomerulopathy (LMGN). We investigated the spatial arrangement of immunoglobulin G (IgG) and C3c fraction of complement (C3c) in the immune deposits of MGN and LMGN with confocal laser scanning microscopy to correlate specific patterns of IgG-C3 interactions with different diseases. Ten patients with MGN and 8 patients with LMGN (World Health Organization class VB) were selected. A determination of the spatial arrangement of the two fluorochromes and the glomerular area occupied by each fluorochrome was performed for each case. Our results showed MGN specimens have an orderly distribution of IgG and C3c, with each deposit showing an outer ring of sole IgG. IgG was always more abundant than C3c (1,619 +/- 271 v 790 +/- 105 micrometer(2), P = 0.002). In LMGN, IgG and C3c were haphazardly arranged, with deposits made of C3c only and an outer ring of IgG only rarely present. Also, the relative amounts of the two antigens were variable, and two groups could be identified (group 1: IgG, 5,515 +/- 1,179 micrometer(2) v C3c, 4,810 +/- 1,174 micrometer(2); P = 0.02; group 2: IgG, 3,358 +/- 658 micrometer(2) v C3c, 4,047 +/- 740 micrometer(2); P = 0.03). Our data show that diffuse IgG capping of the subepithelial immune deposits is diagnostic of MGN. The absence of an orderly three-dimensional arrangement in LMGN deposits (ie, outer ring of IgG) is likely to render active complement components more readily available to inflammatory activities.

Malondialdehyde, lipofuscin and activity of antioxidant enzymes during physical exercise in patients with essential hypertension.

To clarify the role of oxidative damage in essential hypertension, levels of lipid peroxidation products (malondialdehyde and lipofuscin) and activity of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) were examined during a short period of physical exercise. We studied 11 male patients with mild to moderate essential hypertension in World Health Organization classes I or II and 10 healthy male controls. Physical exercise was performed on a bicycle ergometer at graded intensities of 1.0, 1.5 and 2.0 W/kg body weight Plasma concentrations of lipofuscin, malondialdehyde, epinephrine, norepinephrine, insulin, free fatty acids and glucose were determined. Superoxide dismutase activity was analysed in erythrocytes and glutathione peroxidase activity in whole blood. Concentrations of lipofuscin and malondialdehyde were significantly elevated in hypertensive patients. Superoxide dismutase activity was not different between groups, while glutathione peroxidase activity was significantly decreased in hypertensive subjects. During exercise, the concentration of malondialdehyde and antioxidant enzyme activities increased significantly in both groups. No differences were found in absolute increases between the normotensive and hypertensive subjects. The levels of glucose, insulin and free fatty acids were similar in both groups. Basal concentrations of catecholamines and also the exercise-induced increases were lower in hypertensive patients. Our results indicate increased oxidative damage in patients with essential hypertension, which might be caused by a decrease in the activity of glutathione peroxidase. The ability of superoxide dismutase and glutathione peroxidase to respond to increased production of reactive oxygen species during a short period of physical exercise was not impaired in hypertensive subjects.

NaCl sensitivity of essential hypertensive patients is related to insulin resistance.

To evaluate insulin sensitivity of essential hypertensive patients with different salt sensitivities of blood pressure in the absence of confounding factors such as obesity, glucose intolerance and the inclusion both of normotensive and of hypertensive subjects that have affected most previous studies. Ninety-nine patients with untreated mild or moderate essential hypertension, World Health Organization class I-II, participated in the study. Salt sensitivity was estimated using the Weinberger protocol with minor modifications and the patients were classified into tertiles of salt sensitivity. Patients with high NaCl sensitivities were slightly older and had somewhat higher blood pressures than did subjects with low salt sensitivities. Plasma renin activity significantly decreased with increasing salt sensitivity. There were no differences among the three groups in terms of body mass index, fasting blood glucose and insulin plasma levels. There were no differences among the groups in the integrated glucose and insulin response to a standard oral-glucose tolerance test However, there was a significant difference in insulin sensitivity between two subgroups of the upper and lower tertile of salt sensitivity, the salt-sensitive hypertensives having a markedly lower utilization of glucose than did the salt-resistant ones, with a minor overlap (5.4 +/- 0.6 versus 7.4 +/- 0.3 mg/kg per min, P < 0.01). This study showed that essential hypertensive patients with high NaCl sensitivities were relatively insulin resistant compared with those with low NaCl sensitivities, independently of confounding factors such as age, obesity and glucose intolerance. Insulin resistance was not associated with overt hyperinsulinaemia among these patients.