What can we do about patients presenting with myeloma and severe renal failure? Observations from the UK MERIT plasma exchange trial.

Myeloma patients presenting with renal failure continue to have a poor prognosis despite significant advances in anti-myeloma therapy. MERIT was a randomised clinical trial (RCT), set up to evaluate if mechanical reduction of elevated free light chain levels (FLC) would result in clinical benefit. Completion of the planned seven plasma exchanges (PEs) in the first 14 days failed to show, for the exchange group, a greater reduction in FLC or any improvement in dialysis independence at 100 days or subsequently. To improve prognosis for these patients requires earlier diagnosis and prompt anti-myeloma therapy with effectiveness guided by frequent FLC monitoring.

ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse.

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.

Renal function and ear, nose, throat involvement in anti-neutrophil cytoplasmic antibody-associated vasculitis: prospective data from the European Vasculitis Society clinical trials.

OBJECTIVE: We investigated whether ENT involvement is associated with renal biopsy findings and renal function in patients with ANCA-associated vasculitis (AAV). METHODS: Newly diagnosed AAV patients derived from three international, multicentre trials were included. To investigate an association between ENT involvement and estimated glomerular filtration rate (eGFR) at diagnosis and 5-year follow-up, we performed multivariable regression analyses including clinical and histopathological parameters. To investigate whether our findings are specific to ENT involvement, we performed comparable analyses between eGFR and other early disease manifestations (arthralgia/arthritis, cutaneous and lung involvement). RESULTS: One hundred and eighty-five of the 414 patients had ENT involvement. The mean presenting eGFR of patients with and without ENT involvement was 39.16 and 23.88 ml/min/1.73 m(2), respectively (P < 0.001). Mean eGFR increased by 6.76 ml/min/1.73 m(2) with each added ENT symptom (P = 0.007). Patients with ENT involvement had less interstitial fibrosis and tubular atrophy and a prognostically more favourable histopathological class on renal biopsy examination. Multivariable regression analyses correcting for clinical and histopathological parameters showed that ENT involvement is associated with both baseline and 5-year follow-up eGFR. There were no associations between baseline and 5-year follow-up eGFR and arthralgia/arthritis, cutaneous or lung involvement, suggesting that our findings are specific to ENT involvement. CONCLUSION: The presence of ENT involvement in AAV patients is associated with prognostically favourable renal biopsy findings and better renal function. These results indicate that there may be different phenotypes of AAV defined by ENT involvement.

Interstitial lung disease and ANCA-associated vasculitis: a retrospective observational cohort study.

OBJECTIVES: ANCA-associated vasculitis and interstitial lung disease (ILD) are uncommon conditions. The occurrence of both diseases in the same patient is increasingly recognized. Our aim was to ascertain the characteristics and outcomes of patients with ILD and ANCA-associated vasculitis. METHODS: A retrospective observational cohort study was performed. Patients who presented to the Hammersmith Hospital, London, with ANCA-associated vasculitis [granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis (MPA) or Churg-Strauss syndrome] who also had ILD were included. Following hospital discharge, all patients were followed up in a multi-disciplinary vasculitis clinic. We recorded patient demographics, diagnostic tests, treatment, complications and mortality. RESULTS: ILD was observed in 2.7% (n = 14) of our patients with ANCA-associated vasculitis (n = 510); all had MPO-ANCA and a clinical diagnosis of MPA, giving a prevalence of 7.2% in patients with MPA (n = 194). There was no significant difference in survival between patients with MPA and ILD and those with MPA alone. CONCLUSION: It is important that physicians are aware of this clinical association and the presence of ILD should be considered in all patients with ANCA-associated vasculitis, especially those with MPO-ANCA. The possibility that patients with ILD may subsequently develop features of systemic vasculitis should also be remembered.

The contribution of a pharmacy admissions service to patient care.

The aim of this study was to determine the impact of two specialised admissions pharmacists on an acute medical admissions ward. For a one-week period, contributions made to the medical post-take ward round (PTWR), the number of drug histories taken and interventions made as a result, and the availability of medication needed on discharge were documented. An average of 1.1 contributions per patient were made on the PTWR; a large proportion of these concerned therapeutic choice. Pharmacists also intervened to stop medication due to adverse drug reactions in 12% (n=10) of contributions. Fifty-two drug histories were checked by a pharmacist, resulting in 61 interventions (1.1 interventions per patient). The majority of interventions resulted from the unintentional omission of a regular medication (65%, n=39). Only 24% (n=29) of items needed on discharge had to be dispensed in pharmacy and 33% (n=41) were available as patients' own drugs.

Chances of renal recovery for dialysis-dependent ANCA-associated glomerulonephritis.

In patients who have anti-neutrophil cytoplasm autoantibody (ANCA)-associated glomerulonephritis and are on dialysis at time of diagnosis, renal function is sometimes insufficiently restored by immunosuppressive treatment, which often coincides with potentially lethal adverse effects. This study investigated the clinical and histologic variables that determine the chances of dialysis independence, dialysis dependence, or death after 12 mo in these patients. Sixty-nine patients who had ANCA-associated glomerulonephritis and were dialysis dependent at diagnosis received uniform, standard immunosuppressive therapy plus either intravenous methylprednisolone or plasma exchange. Eleven clinical and histologic variables were assessed. Univariate and binary logistic regression analyses were performed. Predictive parameters were entered into a two-step binary logistic regression analysis to differentiate among the outcomes of dialysis independence, dialysis dependence, or death. The point at which the chance of therapy-related death exceeded the chance of dialysis independence was determined. The chance of recovery exceeded the chance of dying in most cases. Intravenous methylprednisolone as adjunctive therapy plus <18% normal glomeruli and severe tubular atrophy increased the chance of therapy-related death over the chance of dialysis independence. Plasma exchange treatment plus severe tubular atrophy and <2% normal glomeruli increased the chance of therapy-related death over that of dialysis independence. Even with ominous histologic findings, the chance of renal recovery exceeds the chance of therapy-related death when these patients are treated with plasma exchange as adjunctive therapy.

Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.

Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.

Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: A prospective analysis of 100 patients with severe renal involvement.

This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients with ANCA-associated vasculitis and severe renal involvement (serum creatinine >500 micromol/L). One hundred patients who were enrolled in an international, randomized, clinical trial to compare plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed prospectively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic and nine clinical parameters were determined as candidate predictors of renal outcome. The end points were renal function at the time of diagnosis (GFR0) and 12 mo after diagnosis (GFR12), dialysis at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of GFR0 were age (r = -0.40, P = 0.04), arteriosclerosis (r = -0.53, P = 0.01), segmental crescents (r = 0.35, P = 0.07), and eosinophilic infiltrate (r = -0.41, P = 0.04). Prognostic indicators for GFR12 were age (r = -0.32, P = 0.01), normal glomeruli (r = 0.24, P = 0.04), tubular atrophy (r = -0.28, P = 0.02), intraepithelial infiltrate (r = -0.26, P = 0.03), and GFR0 (r = 0.29, P = 0.01). Fibrous crescents (r = 0.22, P = 0.03) were predictive of dialysis at entry. Normal glomeruli (r = -0.30, P = 0.01) and treatment arm (r = -0.28, P = 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both chronic and acute tubulointerstitial lesions predicted GFR12 in severe ANCA-associated glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after 12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who were dialysis dependent at presentation were analyzed separately (r = -0.36, P = 0.01). Normal glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo, indicating that the unaffected part of the kidney is vital in determining renal outcome.

Urinary monocyte chemoattractant protein-1 (MCP-1) is a marker of active renal vasculitis.

BACKGROUND: Macrophage infiltration and cytokine production are important in the pathogenesis of crescentic glomerulonephritis in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis. The aim of this study was to investigate whether urinary levels of chemokines, monocyte chemoattractant protein-1 (MCP-1) and fractalkine, were useful tools for non-invasive assessment of renal vasculitis. METHODS: In a prospective study, concentrations of chemokines were measured in urine and serum samples using specific enzyme-linked immunosorbent assays, and related to the patients' clinical status. Renal expression of MCP-1 was studied by immunohistochemical staining of renal biopsies. RESULTS: Urinary levels of MCP-1 were significantly higher in patients with active (P<0.01) or persistent (P<0.05) renal vasculitis, in comparison with healthy volunteers, control patients, patients with inactive vasculitis and patients with extra-renal disease only. There were no differences in serum concentrations of MCP-1 between these groups. Reduction in urinary MCP-1 levels following treatment preceded the improvement of renal function by a median of 2 weeks. In one patient, rising urinary levels of MCP-1, despite immunosuppressive therapy, was associated with progression to severe renal failure. There were no differences in urinary fractalkine levels between the different groups of patients and controls. Immunohistology of renal biopsies from patients with crescentic glomerulonephritis showed increased staining for MCP-1 in glomerular and interstitial cells. Urinary MCP-1 levels correlated with glomerular, but not tubulointerstitial, macrophage infiltration (P<0.05). CONCLUSIONS: This study shows that measurement of urinary MCP-1, but not fractalkine, is a useful non-invasive technique for the assessment of renal involvement and monitoring the response to therapy in ANCA-associated vasculitis.

A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.

BACKGROUND: The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener's granulomatosis and microscopic polyangiitis. We investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission. METHODS: We studied patients with a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg per deciliter (500 micromol per liter) or less. All patients received at least three months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg per kilogram of body weight per day) or a substitute regimen of azathioprine (2 mg per kilogram per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end point. RESULTS: Of 155 patients studied, 144 (93 percent) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5 percent), seven of them during the first three months. Eleven relapses occurred in the azathioprine group (15.5 percent), and 10 occurred in the cyclophosphamide group (13.7 percent, P=0.65). Severe adverse events occurred in 15 patients during the induction phase (10 percent), in 8 patients in the azathioprine group during the remission phase (11 percent), and in 7 patients in the cyclophosphamide group during the remission phase (10 percent, P=0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with microscopic polyangiitis than among those with Wegener's granulomatosis (P=0.03). CONCLUSIONS: In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.

Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study.

BACKGROUND: Renal involvement is frequently present in antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis and is an important cause of end-stage renal failure (ESRF). METHODS: This retrospective, multicenter, sequential cohort study reports presenting features and outcome of 246 new patients diagnosed in London, UK, between 1995 and 2000. RESULTS: Diagnostic subgroups were microscopic polyangiitis, 120 patients (49%); Wegener's granulomatosis (WG), 82 patients (33%); renal-limited vasculitis, 33 patients (13.5%); and Churg-Strauss angiitis, 11 patients (4.5%). Median age was 66 years, 57% were men, and median creatinine level at presentation was 3.87 mg/dL (342 micromol/L). ANCA was present in 92%. Cumulative patient survival at 1 and 5 years was 82% and 76%, respectively. Mortality was associated with age older than 60 years (P < 0.001), development of ESRF (P < 0.001), initial creatinine level greater than 2.26 mg/dL (200 micromol/L; P = 0.01), and sepsis (P < 0.048). ESRF occurred in 68 patients (28%), of whom 47% died. Fifty-six patients who presented with a creatinine level greater than 5.65 mg/dL (500 micromol/L) survived, and 31 patients (55%) achieved dialysis independence. Relapse occurred in 34% after a median of 13 months and was more common in patients with WG (P = 0.048) and proteinase 3-ANCA (P = 0.034). Leukopenia occurred in 41% and was associated with sepsis (P < 0.001). CONCLUSION: Mortality and morbidity of ANCA-associated systemic vasculitis are improving compared with previous series, but remain high. Renal vasculitis often affects older patients, who have a particularly poor outcome. Early diagnosis improves outcome. Leukopenia, caused by immunosuppressive therapy, should be avoided because of the close association with sepsis and death.

Long-term renal injury in ANCA-associated vasculitis: an analysis of 31 patients with follow-up biopsies.

BACKGROUND: We reported previously that in renal disease in relation to antineutrophil cytoplasm auto-antibodies (ANCA)-associated vasculitis, renal outcome correlates better with the percentage of normal glomeruli than with separate active lesions. This may imply that glomeruli, once affected by necrotizing and crescentic lesions, are irreversibly damaged. We quantified and evaluated the course of renal lesions in the present study. METHODS: We retrospectively analysed 31 patients with renal disease in relation to ANCA-associated vasculitis, all treated with immunosuppressive drugs. In all patients, a renal biopsy was performed at diagnosis. A follow-up biopsy was performed in all patients on the indication of a suspected renal relapse, after a mean interval of 31 months. RESULTS: The mean percentage of normal glomeruli in the renal biopsy did not change over time (29% in the initial and 30% in the follow-up biopsy). The mean percentage of glomeruli with crescents, however, significantly decreased from 57 to 30% (P<0.001). The percentage of glomerulosclerosis significantly increased from 12 to 39% (P<0.001). The data were independent of diagnosis, gender, age, time interval between the biopsies, and treatment. CONCLUSIONS: This is the first study to quantify glomerular changes between two time points in patients with renal vasculitis. Our results suggest that, on average, no new glomeruli are recruited into the active disease process. The sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsies is larger than the percentage of sclerotic glomeruli in the follow-up biopsies. Thus, therapy seems not only to prevent normal glomeruli from being recruited into the active disease process for a certain time, but seems also to allow part of the active lesions to revert into a normal phenotype, although another part of the active lesions will be transformed to a chronic phenotype.