Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab.

OBJECTIVES: Secondary inefficacy with infusion reactions and anti-drug antibodies (secondary non-depletion nonresponse, 2NDNR) occurs in 14% of SLE patients receiving repeated rituximab courses. We evaluated baseline clinical characteristics, efficacy and safety of obinutuzumab, a next-generation humanized type-2 anti-CD20 antibody licensed for haematological malignancies in SLE patients with 2NDNR to rituximab. METHODS: We collated data from SLE patients receiving obinutuzumab for secondary non-response to rituximab in BILAG centres. Disease activity was assessed using BILAG-2004, SLEDAI-2K and serology before, and 6 months after, obinutuzumab 2× 1000 mg infusions alongside methylprednisolone 100 mg. RESULTS: All nine patients included in the study received obinutuzumab with concomitant oral immunosuppression. At 6 months post-obinutuzumab, there were significant reductions in median SLEDAI-2K from 12 to 6 (P = 0.014) and total BILAG-2004 score from 21 to 2 (P = 0.009). Complement C3 and dsDNA titres improved significantly (both P = 0.04). Numerical, but not statistically significant improvements were seen in C4 levels. Of 8/9 patients receiving concomitant oral prednisolone at baseline (all >10 mg/day), 5/8 had their dose reduced at 6 months. Four of nine patients were on 5 mg/day and were in Lupus Low Disease Activity State following obinutuzumab. After obinutuzumab, 6/9 patients with peripheral B cell data achieved complete depletion, including 4/4 assessed with highly sensitive assays. Of the nine patients, one obinutuzumab non-responder required CYC therapy. One unvaccinated patient died from COVID-19. CONCLUSIONS: Obinutuzumab appears to be effective and steroid-sparing in renal and non-renal SLE patients with secondary non-response to rituximab. These patients have severe disease with few treatment options but given responsiveness to B cell depletion, switching to humanized type-2 anti-CD20 therapy is a logical approach.

Bilateral renal hemorrhage due to polyarteritis nodosa wrongly attributed to blunt trauma.

BACKGROUND: A 36-year-old, previously healthy man presented to an accident and emergency department with right-sided abdominal pain 7 days after he sustained a trauma to his right flank. He was using no medication other than over-the-counter analgesics since his injury. INVESTIGATIONS: Complete blood count, serum creatinine measurement, liver function tests, hepatitis B and C screening, abdominal CT, renal angiography, surgical exploration and histology of kidney samples. DIAGNOSIS: Polyarteritis nodosa with Page kidney causing bilateral perirenal hematoma, severe hypertension and renal failure. MANAGEMENT: The patient was severely anemic, and his bleeding was investigated. A 15 x 13 x 12 cm retroperitoneal hematoma was found in the region of the right kidney and the patient underwent unilateral right nephrectomy. 3 weeks after discharge the patient was readmitted with a left-sided perirenal hematoma. Steel-coil embolization of the kidney stopped the bleeding but the patient developed hypertension and renal failure, and antihypertensive agents and dialysis were started. Microaneurysms and vessel-wall necrosis were discovered on re-examination of the angiogram and histology, respectively, so immunosuppressive therapy was started, comprising intravenous methylprednisolone daily for 3 days and oral prednisolone and intravenous cyclophosphamide for 4 weeks. Page kidney, resulting from the bleeding into the solitary kidney, caused stretching of the renal artery and deterioration of renal function, which required hemodialysis treatment.

Rhodococcus equi infection during treatment of a c-ANCA positive vasculitis: a case report.

Rhodococcus equi is a rare form of opportunistic infection in humans, more common in the immunocompromised. We present a case of pulmonary infection and subsequent cerebral abscess secondary to R. equi in a patient receiving immunosuppression for a c-ANCA positive vasculitis. Heightened awareness of R. equi infection is important when considering immunocompromised patients presenting with sepsis, especially those with cavitating pulmonary lesions and normal respiratory commensals on culture. Delays in diagnosis and treatment can cause increased patient morbidity and mortality.

The ratio of extracellular fluid to total body water and technique survival in peritoneal dialysis patients.

BACKGROUND: Patients receiving peritoneal dialysis experience a high technique failure rate and are often overhydrated. We examined whether an increased extracellular fluid volume (VECF) as a proportion of the total body water (VTBW) predicted technique survival (TS) in a prevalent patient cohort. METHODS: The VECF and VTBW were estimated by multiple-frequency bioelectric impedance in 59 prevalent peritoneal dialysis patients (median time on dialysis 14 months). Demographic, biochemical (albumin, C-reactive protein, and ferritin), and anthropometric data, forearm muscle strength, nutritional score by three-point Subjective Global Assessment, residual renal function, dialysate-to-plasma (D/P) creatinine ratio, total weekly Kt/V urea, total creatinine clearance, normalized protein equivalent of nitrogen appearance, and midarm muscle circumference were also assessed. Technique survival was determined at 3 years, and significant predictors of TS were sought. RESULTS: In patient groups defined by falling above or below the median value for each parameter, only residual renal function (p = 0.002), 24-hour ultrafiltrate volume (p = 0.02), and VECF/VTBW ratio (p = 0.05) were significant predictors of TS. Subjects with a higher than median VECF/VTBW ratio had a 3-year TS of 46%, compared to 78% in subjects with a lower than median value. In multivariate analysis, systolic blood pressure and VECF/VTBW ratio (both p < 0.05) were significant predictors of TS. C-reactive protein approached significance. CONCLUSION: Increased ratio of extracellular fluid volume to total body water is associated with decreased TS in peritoneal dialysis.

Is subjective global assessment a reliable measure of nutritional status in hemodialysis?

OBJECTIVE: Subjective global assessment (SGA) is recommended in US and European guidelines for the nutritional assessment of patients with end-stage renal failure (ESRF). SGA identifies patient groups with abnormal nutritional parameters, but may fail to identify patients with malnutrition as identified by other techniques, such as total body nitrogen. We sought to compare SGA with a composite nutritional score. METHODS: HD patients were assessed by SGA, anthropometry, 3-day food diary, serum albumin, Kt/V urea, and normalized protein catabolic rate (nPCR). A composite nutritional score was derived from SGA, body mass index, percent of reference weight, triceps skinfold, midarm muscle circumference, and serum albumin. RESULTS: In 72 HD patients an abnormal SGA identified a patient group with reduced midarm circumference, midarm muscle circumference and serum creatinine and an increased composite nutritional score. However, overlap of nutritional scores was considerable between the normal and abnormal SGA groups, suggesting that SGA misclassified a large number of subjects. Serum albumin correlated with C-reactive protein (r = -0.473, P <.0001), not nutritional status. The composite nutritional score correlated with all of its components except for serum albumin. CONCLUSIONS: SGA may not reliably identify hemodialysis patients with abnormal nutrition. Serum albumin is related to inflammation and not to nutrition status.

Unusual iron(III) ate complexes stabilized by Li-pi interactions.

Several iron(III) complexes incorporating diamidoether ligands are described. The reaction between [Li(2)[RN(SiMe(2))](2)O] and FeX(3) (X=Cl or Br; R=2,4,6-Me(3)Ph or 2,6-iPr(2)Ph) form unusual ate complexes, [FeX(2)Li[RN(SiMe(2))](2)O](2) (2, X=Cl, R=2,4,6-Me(3)Ph; 3, X=Br, R=2,4,6-Me(3)Ph; 4, X=Cl, R=2,6-iPr(2)Ph) which are stabilized by Li-pi interactions. These dimeric iron(III)-diamido complexes exhibit magnetic behaviour characteristic of uncoupled high spin (S= 5/2 ) iron(III) centres. They also undergo halide metathesis resulting in reduced iron(II) species. Thus, reaction of 2 with alkyllithium reagents leads to the formation of iron(II) dimer [Fe[Me(3)PhN(SiMe(2))](2)O](2) (6). Similarly, the previously reported iron(III)-diamido complex [FeCl[tBuN(SiMe(2))](2)O](2) (1) reacts with LiPPh(2) to yield the iron(II) dimer [Fe[tBuN(SiMe(2))](2)O](2) but reaction with LiNPh(2) gives the iron(II) product [Fe(2)(NPh(2))(2)[tBuN(SiMe(2))](2)O] (5). Some redox chemistry is also observed as side reactions in the syntheses of 2-4, yielding THF adducts of FeX(2): the one-dimensional chain [FeBr(2)(THF)(2)](n) (7) and the cluster [Fe(4)Cl(8)(THF)(6)]. The X-ray crystal structures of 3, 5 and 7 are described.

The relationship between serum albumin and hydration status in hemodialysis patients.

OBJECTIVE: A decreased serum albumin level predicts poor survival in end-stage renal failure. Hypoalbuminemia is multifactorial and related to poor nutrition, inflammation, and comorbid disease. Overhydration is also common in renal replacement therapy patients, and hemodilution may also contribute to a low serum albumin level. DESIGN: Crosssectional observational study. SETTING: Outpatient hemodialysis unit of a district general hospital. SUBJECTS: We investigated the relationship of serum albumin to C-reactive protein (CRP) and hydration state in 49 unselected hemodialysis patients (28 men). METHODS: Patients were assessed predialysis and postdialysis at their clinical dry weight. Extracellular fluid volume (Vecf) and total body water (Vtbw) were estimated by whole-body bioelectric impedance. Vecf was expressed as a percentage of Vtbw (Vecf%Vtbw). Predialysis CRP, predialysis and postdialysis serum albumin, and body weight were measured. Normalized protein catabolic rate (nPCR) and KT/V urea were calculated. RESULTS: Predialysis and postdialysis serum albumin levels were 36.9 g/L (95% CI, 35.7 and 38.1) and 41.4 g/L (95% CI, 39.7 and 43.3), respectively (P <.0001). Mean weight change was 2.0 +/- 1.2 kg. Predialysis and postdialysis serum albumin levels were negatively correlated with CRP (before: r = -0.393, P <.005; after: r = -0.445, P =.001) and positively with nPCR (before: r = 0.336, P =.018; after: r = 0.353, P =.013). Predialysis serum albumin level correlated with predialysis Vecf%Vtbw (r = -0.384, P =.006) and postdialysis serum albumin level with postdialysis Vecf%Vtbw (r = -0.654, P <.0001). In multivariate analysis, predialysis albumin was dependent on nPCR (P =.04), CRP (P <.0001), and predialysis Vecf%Vtbw (P =.002), and postdialysis albumin was dependent on nPCR (P =.01), CRP (P =.002), and postdialysis Vecf%Vtbw (both P <.0001). The increase in albumin was strongly correlated with both change in actual weight (r = -0.651, P <.0001) and change in Vecf%Vtbw (r = -0.684, P <.0001). CONCLUSION: In unselected hemodialysis patients, serum albumin level is dependent on nPCR, CRP, and extracellular fluid volume. This relationship persists after dialysis, suggesting that many patients remain fluid overloaded at their postdialysis dry weight.

Can a reduction in extracellular fluid volume result in increased serum albumin in peritoneal dialysis patients?

Serum albumin predicts survival in end-stage renal failure. The literature has emphasized the dependence of albumin on inflammation. We previously proposed an independent relationship with overhydration. To date, there is no proven therapy that increases serum albumin in dialysis patients. We investigated whether decreasing dry weight increases serum albumin in peritoneal dialysis patients. Twenty-one subjects (15 continuous ambulatory peritoneal dialysis patients and 6 continuous cycled peritoneal dialysis patients) were assessed at 0 and 4 weeks. Body weight, blood pressure, 4-site skin-fold thickness, subjective global assessment score, and use of antihypertensive medication were recorded. Fluid samples were collected for estimation of serum albumin, C-reactive protein, and 24-hour dialysate and urine volume. The extracellular fluid volume was estimated by multiple-frequency bioelectric impedance. Between the 0- and 4-week assessments, dialysis prescription was altered to increase the daily ultrafiltrate volume (1.00 +/- 0.71 L to 1.29 +/- 0.75 L; P = 0.04). Significant decreases were seen in body weight (70.7 +/- 12.1 kg to 69.9 +/- 12.2 kg; P = 0.0002), extracellular fluid volume (16.2 +/- 3.3 L to 15.5 +/- 3.2 L; P = 0.0006), systolic blood pressure (147.7 +/- 26.3 mm Hg to 124.2 +/- 20.9 mm Hg; P < 0.0001), diastolic blood pressure (84.2 +/- 14.5 mm Hg to 76.6 +/- 11.7 mm Hg; P = 0.01), and number of antihypertensive drugs (1.9 +/- 1.0 to 1.6 +/- 1.1; P = 0.02). Serum albumin increased (34.6 +/- 4.1 g/L to 35.9 +/- 3.6 g/L; P = 0.01). C-reactive protein did not change. Decreasing dry weight in peritoneal dialysis by an increase in ultrafiltration volume results in a decreased extracellular fluid volume, which is reflected by an improvement in blood pressure control. This improvement in blood pressure was associated with an increase in serum albumin. This finding strengthens the argument that overhydration is a cause of hypoalbuminemia in peritoneal dialysis and offers a therapeutic option in management of this patient group.