Rituximab in relapsing and de novo MPO ANCA-associated vasculitis with severe renal involvement: a case series.

BACKGROUND: Antineutrophil cytoplasmic antibody associated vasculitis (AAV) is a group of diseases associated in most cases with the presence of anti-neutrophil cytoplasmic antibodies (ANCAs). Rituximab- based remission induction has been proven effective in ANCA associated vasculitis but scarce data exist in forms with severe renal involvement. In this case series, we report the outcomes in patients with de novo or recurrent MPO-AAV and severe renal involvement treated with rituximab without cyclophosphamide (CYC). METHODS: In this single centre retrospective study, we analysed patients with a clinical diagnosis of de novo or recurrent AAV who met the following criteria: detection of P-ANCA, creatinine clearance lower than 30 ml/min, induction of remission therapy with rituximab without concomitant CYC and a follow up period of at least 6 months. The primary outcomes were complete remission after induction therapy, renal function recovery and mortality after the induction treatment. RESULTS: Eight patients met the inclusion criteria. The M:F ratio was 1:7, the average age was 54 years old and the median follow up was 10 months (7-72); in 2 patients there was a MPA renal limited vasculitis. A renal biopsy was performed in 7 patients. The median BVAS score at rituximab induction was 14(range 6-21). Two patients required haemodialysis before the induction treatment. Four patients developed end stage renal disease (ESRD) that required haemodialysis. These data show a remission of the disease, associated with a stabilization of the kidney function in 50% of patients. In 3 patients who did not show a response, there was also no response to CYC. CONCLUSIONS: This study shows a partial efficacy of rituximab in renal function recovery and a low risk of infectious complications in patients with MPO vasculitis with severe renal involvement, in particular in the short term. The optimal treatment in this subgroup of patients still has to be established because data are lacking.

Genetic screening for pheochromocytoma: should SDHC gene analysis be included?

PGL3 syndrome is caused by mutations in the SDHC gene. At present, only a few families affected by SDHC mutations have been reported in the literature and in each of them the clinical presentation was characterised by paragangliomas located only in the head and neck regions. No evidence of thoracic or abdominal catecholamine-secreting chromaffin tumours has been reported to date. We report the case of a 15-year-old girl with hypertension and a norepinephrine-secreting abdominal paraganglioma who was found to harbour a novel nonsense SDHC mutation, demonstrating that the clinical presentation of PGL3 syndrome can be more diverse than expected.

Nodular macroglossia with combined light chain and beta-2 microglobulin deposition in a long-term dialysis patient.

We describe a case in which nodular macroglossia, a very rare type of tongue involvement, was associated with the co-deposition of lambda light chain and beta-2 microglobulin fibrils in the tongue. The combined presence of two different amyloid fibrils did not lead to a more unfavourable clinical outcome. We believe that both these features often remain underdiagnosed and are in fact more frequent than reported. A careful clinical examination of the tongue together with serum immunofixation should be routine in all patients with dialysis-related amyloidosis in order to investigate the prevalence and type of tongue involvement and to rule out other types of amyloidosis. In all cases of suspected mixed amyloidosis, immunohistochemical characterization of fibrils should be carried out by electron microscopy.

ANCA in dialysis patients: a role for bioincompatibility?

UNLABELLED: BACKGROUND. Anti-neutrophil cytoplasmic autoantibodies (ANCA) have been described in patients suffering from systemic vasculitis such as Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and other pathological conditions. In this paper we report a greater incidence of ANCA in hemodialysis patients as compared to peritoneal dialysis patients, pre-dialytic uremic patients and non-renal patients; a possible role for dialysis bioincompatibility in ANCA generation was also investigated. METHODS: A total of 335 uremics in substitutive treatment (176 in hemodialytic treatment and 159 in peritoneal dialysis) were examined for ANCA positivity. A total of 189 patients with advanced renal failure in conservative treatment and 100 healthy subjects were used as control. The dialysis techniques were standard hemodialysis (n = 119), low volume hemodiafiltration (n = 26) and hemofiltration (n = 31). ANCA positivity was examined by immunofluorescence (IF): diffuse finely granular staining was considered as classical positive reaction (C-ANCA) and P-ANCA was diagnosed if a perinuclear staining was observed. EIA for proteinase-3 (anti PR-3) and myeloperoxidase-antibodies (anti-MPO) were also performed. RESULTS: In non-renal patients and in patients with pre-dialytic renal insufficiency none were found ANCA positive. In peritoneal dialysis patients all but one were ANCA negative with IF, with all EIA test resulting negative. In hemodialytic patients, a positive IF test was found in 26 (14.7%) for P-ANCA and in 5 (2.8%) for C-ANCA; using the EIA test 23 (13%) patients were positive for MPO and 12 (6.8%) for PR-3. CONCLUSIONS: No correlation with age, primary renal diseases, dialytic age, dialysis membrane materials was found; regarding the different extracorporeal dialytic techniques a higher incidence (p < 0.02) was detected in patients undergoing HDF Backfiltration of contaminated dialysate may induce ANCA via an increased cytokine generation.

Total antioxidant capacity (TAC): is it an effective method to evaluate the oxidative stress in uraemia?

Lipoprotein abnormalities are common in uraemia and are considered important factors for development of atherosclerosis and progression of renal disease. Reduction of total antioxidant capacity (TAC) and lipid peroxidation (LP) probably play a major role in both processes. The aim of this study was to assess the effect of renal function, dietary manipulation and lipids on TAC of uraemic patients with different chronic renal failure (CRF). Sixty patients (36M, 24F), aged 60 +/- 12 years were divided into five groups according to serum creatinine levels (sCr,mg/dl)--CRFI, 1.5-3; CRFII, > 3-5.5; CRFIII, > 5.5; CRFIV, > 3 on vegetarian supplemented diet (SD); CRFV haemodialysis patients (HD)- and investigated for TAC by enhanced chemiluminescent assay, autoantibodies against oxidized LDL (oxLDLAb), lipids, apolipoprotein AI, B, Lp(a) and uric acid (UA). The results were compared to a control group of 19 people (8M, 11F), aged 52 +/- 11 years with sCr < 1.5. TAC increased significantly with the progression of CRF and was strongly related to both sCr and UA. Lipids and SD did not show any influence on TAC. Unexpectedly, lipid peroxidation did not correlate to TAC, neither to sCr or UA. HD accounted for a mild reduction of both TAC and LP. Patients on SD showed a marked reduction of LP as compared to patients with a similar degree of renal failure (CRF-III) but on conventional diet. Our results suggest that elevated TAC in uraemia is likely to be dependent on increased UA levels and does not seem to induce an effective protection in vivo from oxidative stress. In conclusion, TAC does not appear to be a reliable method for assessing the oxidative susceptibility of CRF patients.

Mechanisms of acid-base homeostasis in acetate and bicarbonate dialysis, lactate hemofiltration and hemodiafiltration.

The different mechanisms of acidosis buffering were investigated in 15 RDT patients dialyzed in cross-over with four depurative techniques: acetate dialysis (AD), bicarbonate dialysis (BD), lactate hemofiltration (LHF) and hemodiafiltration (HDF) with acetate bath and lactate reinfusion fluid. Blood pH, bicarbonate, blood gases, intraerythrocytic pH - on red cell hemolisates - anion gap, L-lactate, pyruvate, adenosinmonophosphate (ADP) and 2-3 Diphosphoglycerate (2-3 DPG) levels were evaluated. During AD the intradialytic buffering is initially achieved by the CO2 fall and later by the acetate metabolism and an important bicarbonate shift from the intra to the extracellular space. A physiological compensation is obtained during BD with bicarbonate administration and a mild ventilatory response to the pCO2 increase. In LHF the massive lactate administration, with plasma levels of 7 mmol/l, strongly alters the Central Nervous System elettroneutrality inducing a hyperventilatory response with a purely pulmonary acidosis buffering. Furthermore the lactate/pyruvate ratio rose as high as 40:1 with ADP increase and cellular energy depletion. In HDF several different mechanisms are associated: the CO2 fixation, the acetate muscular metabolism, the intra-extracellular bicarbonate shift with the pulmonary response driven by lactate Central Nervous System penetration.

Intravenous immunoglobulin therapy of membranous nephropathy: efficacy and safety.

Preliminary results of the efficacy of high-dose intravenous human IgG in patients with biopsy-confirmed idiopathic membranous nephropathy (IMGN) were reported. Five patients with normal renal function (creatinine clearance 125.2 +/- 16 ml/min/1.73 m2 BSA) (Group A) and 4 patients with moderate renal insufficiency (creatinine clearance 65.5 +/- 8.3 ml/min/1.73 m2 BSA) (Group B) received pulse doses of IgG (0.4 g/kg BW) for 3 consecutive days; these 3-day boli were repeated 3 times at 21-day intervals; since then for a 10-month period one bolus once every 3 weeks has been administered. Five responder patients at the end of the trial received a new renal biopsy. In 4 Group A patients complete remission of proteinuria (daily proteinuria less than 0.2 g) was observed, whereas 1 patient showed partial remission (proteinuria 2 g/day). In Group B patients, 1 showed complete remission and 2 partial remission; in 1 patient no variation of proteinuria was noted. In responder patients clinical and biological findings of the nephrotic syndrome disappeared and a statistically significant increase of creatinine clearance was observed. In control biopsies at the end of the trial the immunofluorescence staining failed to find immunodeposits and recovery of glomerular lesions at light microscopy. In conclusion, IgG therapy seems to be of benefit to patients with IMGN but a randomized clinical trial to confirm this preliminary report is needed.

[Cisplatin nephrotoxicity: effects on fractional excretion of sodium and enzymuria]. / Nefrotossicità del cisplatino. Effetto sull'escrezione frazionale del sodio e sulla enzimuria.

The effects (in five therapeutic cycles) of Cisplatin on urinary enzyme excretion (specific markers of tubular damage), fractional excretion of sodium, fractional reabsorption of phosphate, serum Creatinine and creatinine Clearance were assessed in 17 female patients with ovarian carcinoma. An immediate reduction of sodium fractional excretion was observed: this appears a more sensible Cisplatin-nephrotoxicity marker than serum Creatinine and creatinine Clearance. No significant variations were noted in fractional reabsorption of phosphate or urinary Lysozyme and Beta-2-microglobulin but there was a significant increase of other urinary enzymes, confirming the potential nephrotoxicity of DDP treatment.