Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the least studied of the causes of idiopathic nephrotic syndrome, and there are few specific guidelines for treatment. AIM: To review data from five UK renal units to investigate whether adult patients with FSGS were treated uniformly, and to examine the effect of treatment on proteinuria and survival. DESIGN: Retrospective record review. METHODS: We examined electronic records of patients with idiopathic FSGS for information on baseline clinical parameters, treatment regimens and outcomes. RESULTS: Of 136 patients with primary FSGS and nephrotic range proteinuria, 76 (56%) were treated with prednisolone and of this group, 59% were treated with additional immunosuppression. Among the treated patients, the total remission rate (complete and partial) was 67%, and one hospital achieved a remission rate of 80%. Treated patients had a significantly higher remission rate than those who were not treated. Remission was associated with a 5-year survival off dialysis of 94%, compared with 53% if remission was not achieved. Baseline serum creatinine and remission were independently associated with survival off dialysis in a multivariate Cox proportional hazards model. DISCUSSION: Patients with primary FSGS and nephrotic range proteinuria, who are treated with corticosteroids, are more likely to enter remission than those who are not treated. Remission rates of up to 80% can be achieved with prolonged treatment, and remission is an independent predictor of survival off dialysis. Patients who do not achieve remission have a poor prognosis. Further clarification of optimal treatment regimens requires additional, prospective studies.

Diagnosing Pneumocystis carinii pneumonia by cytological examination of bronchoalveolar lavage fluid: report of 15 cases.

Sixty episodes of pneumonia occurring in 53 immunosuppressed patients were investigated by bronchoalveolar lavage. Pneumocystis carinii was diagnosed on 15 (25%) occasions. In all cases the Papanicolaou stained lavage fluid presented a distinctive appearance and contained abundant, often biphasic, staining, "honeycomb" debris, and few alveolar macrophages. The Grocott methenamine silver technique confirmed the presence of characteristic cystic organisms in the debris in all 15 instances. Cysts containing internal sporozoites were identified in Gram stained material only with difficulty. Neither May-Grünwald-Giemsa stain nor fluorescence microscopy under ultraviolet light were effective for routine investigation.

Glomerular vascular cell adhesion molecule-1 expression in renal vasculitis.

AIMS: To study the expression of cell adhesion molecules in the renal biopsy specimens of patients with systemic vasculitis and Henoch-Schönlein purpura (HSP); to correlate this with the severity of glomerular inflammation. METHODS: Renal biopsy specimens obtained from eight patients with untreated systemic vasculitis (four with Wegener's granulomatosis and four with microscopic polyarteritis), eight with HSP and nine controls (four with normal histopathology and five with thin glomerular basement membrane disease) were stained using the alkaline phosphatase anti-alkaline phosphatase method with monoclonal antibodies directed against intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. RESULTS: Biopsy specimens of normal kidneys expressed ICAM-1 in glomerular endocapillary cells, Bowman's capsule epithelium, interstitial cells and interstitial vascular endothelium, and VCAM-1 in Bowman's capsule epithelium, proximal tubular epithelium and interstitial vascular endothelium. No staining with antibody directed against E-selectin was seen in any of the biopsy specimens. Biopsy specimens of patients with a vasculitic glomerulonephritis (segmental necrotising glomerulonephritis) expressed VCAM-1 in glomerular endocapillary cells (four of eight patients with systemic vasculitis; two of eight patients with HSP). In patients with a systemic vasculitis glomerular VCAM-1 expression was associated with a more severe renal lesoin (44, 50, 60, and 65% of glomeruli involved) than in those not showing glomerular VCAM-1 expression (3, 3, 11, and 39% of glomeruli involved). CONCLUSION: Expression of VCAM-1 by glomerular endocapillary cells in renal biopsy specimens raises the possibility that recruitment of VLA-4 bearing leucocytes may contribute to glomerular injury in Wegener's granulomatosis and microscopic polyarteritis.

Anti-epithelial (anti-A549) antibodies: their nature, specificity and relevance to transplantation.

Several studies have addressed the possible importance of anti-epithelial cell antibodies in kidney transplantation using the A549 cell line as an in vitro model. In this paper we report our results using for the first time an enzyme-linked immunosorbent assay (ELISA) to detect the anti-A549 cell antibodies. Sera from 129 kidney transplant patients were tested for IgM anti-epithelial cell antibodies directed against the A549 cell line prior to transplantation; only three sera were positive (2.3%). 101 of these patients were then followed-up post-transplantation; sera were collected routinely at 2, 6 and 12 weeks and at the time of rejection episodes. All samples were also tested for cytomegalovirus (CMV) IgM antibodies. Sixteen patients developed anti-A549 IgM antibodies, and there was no correlation with acute graft rejection. Anti-epithelial antibodies showed no binding to sections of normal kidney or biopsies of rejected kidneys. Eleven patients were positive for anti-CMV IgM antibodies. In nine cases both IgM anti-A549 and IgM anti-CMV antibodies were found, which was a highly significant association (p < 0.001). Analysis of A549 cellular proteins by immunoblotting gave evidence for the presence of CMV polypeptides in the cell lysate. Electron-microscopic examination of A549 cell preparations revealed intracellular particles which were compatible in size with CMV. Polymerase chain reaction analysis confirmed the presence of a specific CMV DNA sequence in A549 cells of several batches from different sources. Our data strongly suggest that the A549 cell line used in several published reports is infected with CMV and that in the majority of cases the anti-A549 'anti-epithelial' antibodies found in renal transplant patients are anti-CMV antibodies.

Powerful morphometric indicator of prognosis in lupus nephritis.

BACKGROUND: Changes in renal biopsies in lupus nephritis have been analysed in many ways, but few have had prognostic value. AIM: To see whether a morphometric measure of chronic renal damage that was a prognostic indicator in other conditions had similar value in lupus nephritis. DESIGN: Retrospective analysis of biopsies and study of outcome. METHODS: On sections of 260 biopsies from 182 consecutive patients with systemic lupus erythematosus, an image analysis system measured chronic damage as a proportion of cortical area, to give the index of chronic damage. This was related to survival (until death or onset of dialysis). Patients were followed for up to 20 years. RESULTS: The index of chronic damage ranged from 0 to 93%. Twenty-three patients (13%) died before dialysis, many from infection or myocardial infarction, and 40 (22%) went onto permanent dialysis. There were strong correlations between the index and time until death or dialysis (log rank test: chi(2) = 51.08, three degrees of freedom [df], p < 0.001) and time to dialysis (log rank test: chi(2) = 72.88, 3df, p < 0.001), but there was no correlation with time until death before dialysis (log rank test: chi(2) = 0.36, 3df, p > 0.9). WHO class of nephritis had no major relation to outcome after the index was taken into account and after appropriate treatment of the different classes. DISCUSSION: The index was a strong indicator of risk of progression to renal failure in lupus nephritis, but not of risk of death before dialysis. This will be useful in clinical management and treatment trials.

Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis.

The continuing morbidity of patients with vasculitis, despite the improved prognosis with aggressive therapy, underlines the need for accurate disease assessment. We have devised a clinical index of disease activity, and evaluated its use in several forms of necrotizing vasculitis. The weighted score is based on symptoms and signs in nine separate organ systems. Disease features are only scored if they are attributable to active vasculitis. The Birmingham Vasculitis Activity Score (BVAS) was compared with two other published vasculitis activity scores, with the physician's global assessment (PGA), with outcome, and with serological markers of disease activity. In a cross-sectional study of 213 consecutive patients with different forms of vasculitis, all 107 vasculitis patients who were judged completely well on clinical assessment had a BVAS score of 0. Twenty-two patients with active vasculitis prior to treatment had a median score of 7.5 (range 4-30) and 69 with active disease on treatment had a median score of 10 (1-29). Of the 12 who died, median score immediately prior to death was 20.5 (9-30). In a serial prospective study, 30 cases had documented episodes of active disease. During periods of disease activity, the median BVAS values were significantly higher than in remission (15 [range 3-32] vs. 0 [0-2], p < 0.001); the same was true for CRP values (80 [9-361] vs. 13.5 [5-68], p < 0.001). This was not true for erythrocyte sedimentation rate (ESR), haemoglobin (Hb) or von Willebrand factor (VWF).(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis.

Although cyclophosphamide and prednisolone are effective in treating systemic vasculitis, the optimum treatment regimes and duration of treatment are unknown. We randomized 54 patients aged 15-70 years (median 57.5 years) with systemic vasculitis (classical polyarteritis n = 8, microscopic polyarteritis n = 17, Wegener's granulomatosis n = 29) to treatment with either pulse cyclophosphamide and prednisolone (PCYP) (n = 24) or continuous oral and prednisolone and cyclophosphamide, with the latter followed after a median of 3 months (range 1.5-10 months) by azathioprine (CCAZP) (n = 30). Patients on CCAZP were more likely to develop leucopenia (13/30) than patients on PCYP, (7/24) although the difference was not significant. The numbers of infective episodes during follow up were comparable in the two groups at 1.7/patient for PCYP and 1.66/patient for CCAZP. Overall, 26/30 patients (87%) treated with CCAZP developed treatment-related toxicity, as did 17/24 patients (71%) treated with PCYP. After a median follow-up of 40.4 months (range 0.7-64.8), there was no difference in the frequency of deaths (PCYP 5, CCAZP 4), relapses (PCCYP 7, CCAZP 8), treatment failures (PCYP 4, CCAZP 4), improvement in disease activity scores or renal function. Survival at three years was 77% in patients treated with PCYP, and 90% in patients on CCAZP (p = 0.38). There was a tendency towards increased toxicity in patients treated with the continuous regimen.

Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity.

Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents. This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2 g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein (CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3 months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively (p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2 weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group. A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3 months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with persistent disease activity after standard therapy.

Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis.

We report ten patients with rheumatoid arthritis (RA) who developed a focal segmental necrotizing glomerulonephritis (FSNGN) and extracapillary proliferation typical of vasculitic glomerulonephritis. Five patients also had extrarenal vasculitis. Renal presentation was with renal impairment (n = 9) (median creatinine 726 mumol/l, range 230-1592 mumol/l), microscopic haematuria (n = 8) and proteinuria (n = 10). Nine patients were seropositive for rheumatoid factor and nine had bone erosions. Serum from four of five patients tested by indirect immunofluorescence was positive for antineutrophil cytoplasmic antibody (ANCA) with perinuclear staining. Only three patients had penicillamine or gold therapy. Treatment was with prednisolone and cyclophosphamide (six patients, two of whom were also plasma-exchanged), prednisolone and azathioprine (two patients) and prednisolone alone (two patients). There was a marked improvement in renal function in eight patients. Two patients with dialysis-dependent renal failure recovered renal function, although in one patient this was transient and she required further dialysis 4 months later. Two other patients progressed to dialysis at 3 months and 1 year respectively. Four patients died, one remains dialysis-dependent, and four continue to have good renal function at 5 year follow-up (median creatinine 148.5 mumol/l, range 120-193 mumol/l). One patient was lost to follow-up at 5 years. FSNGN should be considered in all patients with RA and renal impairment, proteinuria and/or microscopic haematuria. This diagnosis appears to be more likely in patients with clinical extrarenal vasculitis, bone erosions or who are seropositive. In these cases, an urgent renal biopsy is indicated.

Disinfection of hands and tubing of CAPD patients.

During a 3 month study the effectiveness of two methods of handwashing was assessed in a group of 31 patients undergoing continuous ambulatory peritoneal dialysis. A defined, double rinse with alcohol, prior to bag exchange, was found to be more convenient and significantly more effective than povidone-iodine alone or povidone-iodine followed by alcohol. Spraying the tubing around the bag connector with 70 per cent ethanol reduced the numbers of adherent skin organisms so reducing the likelihood of bacteria being drawn into the dialysate. Although there was no difference in the overall incidence of peritonitis in the two groups of patients studied, there was an unexpected drop in the incidence of peritonitis caused by coagulase-negative skin staphylococci. This was attributed to an overall awareness of the importance of handwashing and aseptic procedures during bag exchange. Monitoring the bacteriology of the catheter exit site may give some prior indication as to the likelihood of subsequent peritonitis especially with Staphylococcus aureus and Gram-negative bacilli.

Improving prescribing using a rule based prescribing system.

OBJECTIVE: To test the hypothesis that the prescribing behaviour of doctors would improve after having experience with a computerised rule based prescribing system. DESIGN: A prospective observational study of changes in prescribing habits resulting from the use of a computerised prescribing system in (1) a cohort of experienced users compared with a new cohort, and (2) a single cohort at the beginning and after 3 weeks of computer aided prescribing. SETTING: 64 bed renal unit in a teaching hospital. INTERVENTION: Routine use of a computerised prescribing system by doctors and nurses on a renal unit from 1 July to 31 August 2001. MAIN OUTCOME MEASURES: Number of warning messages generated by the system; proportion of warning messages overridden; comparison between doctors of different grades; comparison by doctors' familiarity with the system. RESULTS: A total of 51,612 records relating to 5995 prescriptions made by 103 users, of whom 42 were doctors, were analysed. The prescriptions generated 15,853 messages, of which 6592 were warning messages indicating prescribing errors or problems. Doctors new to the system generated fewer warning messages after using the system for 3 weeks (0.81 warning messages per prescription v 0.42 after 3 weeks, p = 0.03). Doctors with more experience of the system were less likely to generate a warning message (Spearman's rho = -0.90, p = 0.04) but were more likely to disregard one (Spearman's rho = -1, p<0.01). Senior doctors were more likely than junior doctors to ignore a warning message. CONCLUSIONS: Doctors are influenced by the experience of using a computerised prescribing system. When judged by the number of warning messages generated per prescription, their prescribing improves with time and number of prescriptions written. Consultants and registrars are more likely to use their clinical judgement to override warning messages regarding prescribed drugs.

Hypertension and end-stage renal failure in tropical Africa.

We report clinical data and autopsy renal histology in 78 patients who died from chronic renal failure in Ghana. There were 78 patients, 54 male and 24 female, and the majority were aged between 20 and 50 years. The major causes of chronic renal failure were hypertensive renal damage (38 patients) and chronic glomerulonephritis (33 patients). The most common glomerular lesion leading to end-stage renal failure was a focal segmental sclerosing glomerulonephritis. It is possible that some of these segmental sclerosing glomerular lesions were secondary to glomerular hyperfiltration caused by reduced renal mass from hypertension-induced glomerular ischaemia. A public health programme leading to better awareness of the importance of detecting hypertension and having this treated could be a major contribution to reducing by at least half the number of deaths from renal failure reported here.

Circulating soluble adhesion molecules in inflammatory bowel disease.

OBJECTIVE: To determine levels of soluble forms of the cell adhesion molecules (CAM), ICAM-1, E-Selectin and VCAM-1 in relation to prevalence, treatment and disease activity in inflammatory bowel disease. PATIENTS AND METHODS: Plasma was obtained from patients with ulcerative colitis (n = 49), patients with ulcerative colitis who had undergone restorative proctocolectomy (n = 32, eight of whom had a clinical pouchitis), Crohn's disease patients (n = 34) and 24 healthy controls. RESULTS: Plasma soluble ICAM-1 levels [medians (ranges in ng/ml)] were significantly higher in patients with active ulcerative colitis [270 (90-510)], pouchitis [415 (310-670)] and active Crohn's disease [305 (200-630)] than in those with inactive ulcerative colitis [225 (140-425), P = 0.031], non-inflamed ileoanal pouch [260 (140-380), P = 0.0004] and inactive Crohn's disease [245 (90-520), P = 0.045], respectively, and controls. The soluble E-Selectin levels were also significantly higher in patients with active ulcerative colitis [55 (40-140)], pouchitis [90 (45-145)], and active Crohn's disease [78 (30-115)] than in those with inactive ulcerative colitis [45 (20-80, P = 0.003], non-inflamed ileoanal pouch [45 (20-90), P = 0.001] and inactive Crohn's disease [48 (25-90, P = 0.020], respectively, and controls. CONCLUSIONS: The present study suggests that increased levels of soluble ICAM-1 and soluble E-Selectin occur during active inflammatory bowel disease and pouchitis, which may be used as sensitive markers of continuing inflammation.

Treatment of vasculitic IgA nephropathy.

BACKGROUND: Patients with IgA nephropathy and histological vasculitic/crescentic lesions have a poor prognosis. We performed a retrospective study to assess whether treatment with steroids and immunosuppressants would preserve renal function by healing these lesions and thereby prevent progression to glomerular sclerosis and renal failure. METHODS: Sixteen patients with IgA nephropathy and a vasculitic/crescentic glomerulonephritis diagnosed by renal histology were treated with a reducing course of prednisolone (initial dose 60 mg/day). Six patients also received cyclophosphamide (2 mg/kg/day) for three months followed by azathioprine (100 mg/day) in five patients. Ten patients received azathioprine (100 mg/day) in addition to prednisolone. The median duration of treatment was 12 months (range 5-30 months). At the end of treatment each patient had a second renal biopsy. RESULTS: Following treatment there was a significant reduction in the proportion of glomeruli with acute vasculitic lesions from a median of 17.4% (range 4.8-57.5%) to 0 (range 0-15.8%) (p=0.001). There was an increase in the proportion of globally sclerosed glomeruli from a median of 13.4% (range 0-44.4%) to 21.5% (range 0-90%) after treatment but this did not significantly differ from baseline (p=0.24). The proportion of renal cortex with chronic tubular atrophy increased from 2.55% (0.4-57.7%) to 11.3% (0.3-61%) (p=0.09). The median duration of follow-up was 30 months (inter-quartile range 6-30 months). At both 12 and 24 months there was no significant increase in serum creatinine. Four patients, however, developed end-stage renal failure between 24 and 81 months. CONCLUSION: In this retrospective study we show that treatment with steroids and immunosuppressants leads to healing of vasculitic lesions and may thus arrest progression of glomerular scarring.

IgG subclasses of PEG precipitable IgG in systemic lupus erythematosus sera.

Polyethylene glycol (PEG, 4%)-precipitated macromolecular IgG isolated from the sera of 20 patients with systemic lupus erythematosus (SLE) and 15 control subjects was analyzed for its IgG isotype concentration by single radial immunodiffusion. PEG precipitates from SLE sera had higher mean levels of IgG1, IgG2 and IgG3 and lower IgG4 than PEG precipitates isolated from normal sera although only the IgG2 levels were significantly different. Using an anti-complementary assay there was a significant correlation between the ability of parent sera to fix complement and the absolute levels of PEG precipitable IgG1, IgG2 and IgG3. These data suggest that the ability of immune complexes in the sera of patients with SLE to fix complement is dependent on their IgG subclass composition.

The glomerular tip lesion: a steroid responsive nephrotic syndrome.

The glomerular tip nephropathy is a cause of the nephrotic syndrome and has distinct pathological features. Glomerular tufts appear normal on light microscopy except for a segmental lesion invariably present in all glomeruli at the origin of the proximal tubule. Data on twenty adults whose renal biopsies demonstrated this lesion and who were followed for a mean of 7.4 years are analyzed. Eighteen patients were treated with steroids; ten of these had complete remission of proteinuria and seven a significant reduction of their proteinuria. Ten patients had moderately impaired renal function (serum creatinine greater than 120 mumol/l) at presentation, eight received steroids and achieved a reduction in serum creatinine. The prognosis was good, with no patient developing chronic renal failure requiring dialysis.

Surgical treatment of hydrothorax complicating continuous ambulatory peritoneal dialysis.

Acute hydrothorax is a well recognized complication of continuous ambulatory peritoneal dialysis (CAPD) and is usually regarded as a contra-indication to the further use of this form of dialysis. We report the first case of treatment by surgical closure of a communication between the peritoneal and the right pleural cavity enabling CAPD to continue successfully. The development of an acute hydrothorax on CAPD is therefore not a reason to abandon this form of dialysis and can be treated by a simple thoracic surgical procedure.

Low calcium dialysate and hyperparathyroidism.

A low calcium dialysate reduces hypercalcemia from calcium-containing phosphate binders and makes phosphate control possible without the use of aluminum salts. We asked whether this might, however, lead to hyperparathyroidism. We prospectively studied serum concentrations of parathyroid hormone levels (by an immunoreactive intact molecule assay) in 173 patients on continuous ambulatory peritoneal dialysis (CAPD) who were started on a low calcium dialysate (Ca2+ 1.25 or 1.00 mmol/L) because of hypercalcemia. Median follow-up was 13.2 months (range 1-28). Initial serum parathyroid hormone was [median(range)]: 70(5-1043) ng/L pre low calcium dialysate, and this rose to 130(5-914) ng/L at 0-6 months; 130(5-1030) ng/L at 6-12 months; 170(170-1400) ng/L at 12-18 months; and 130(5-1200) ng/L at 18-24 months (p = 0.0006). Twenty-two patients required a parathyroidectomy because of a sustained rise in parathyroid hormone that was not responsive to alfacalcidol and hypercalcemia. Initial serum parathyroid hormone was significantly higher in these patients at 359 (5-1073) ng/L as compared to a level of 69.5 (6-1147) ng/L in patients who did not have a parathyroidectomy (p = 0.0009). There was a significant sustained fall in mean serum corrected calcium from 2.77 (2.37-3.51) mmol/L to 2.53 (1.39-3.20) mmol/L at three months (p = 0.0006), a nonsignificant rise in mean serum alkaline phosphate from 179 (47-1858) mmol/L to 191 (55-1821) mmol/L (p = 0.15), and a fall in mean serum phosphate levels from 1.87 (0.59-3.18) mmol/L to 1.68 (0.45-3.6) mmol/L (p = 0.76). Our data suggest that the benefits of a low calcium dialysate in CAPD patients are balanced by an increased risk of hyperparathyroidism, and that this risk is higher in patients with an initially high serum parathyroid hormone level.

Pooled human IGG (PHIG) inhibits the binding of anti-myeloperoxidase antibodies to myeloperoxidase.

This study demonstrates that pooled human immunoglobulin (PHIG) contains anti-idiotypes to anti-myeloperoxidase (MPO) antibodies and can inhibit the binding of anti-MPO to MPO. The variability seen in the inhibitory effect of different PHIG preparations in the same and also in different patient sera suggests heterogeneity in the idiotypic repertoire of anti-MPO antibodies.

Little evidence for anti-endothelial-cell antibodies in microscopic polyarteritis and Wegener's granulomatosis.

Sera from patients with a vasculitis and controls were investigated for the presence of anti-endothelial cell antibodies(AECA), anti- neutrophil cytoplasmic antibodies(ANCA) and anti-myeloperoxidase (MPO) antibodies. Only 19% of patients with Wegener's granulomatosis and 2% of patients with microscopic polyarteritis had AECA. Our data suggests that AECA are a minor antibody system in vasculitis.