Real world analysis of high-cut-off (HCO) hemodialysis with bortezomib-based backbone therapy in patients with multiple myeloma and acute kidney injury.

BACKGROUND: In patients with multiple myeloma (MM) free light chain-induced cast nephropathy is a serious complication associated with poor survival. High-cut-off (HCO) hemodialysis can reduce the amount of serum free light chains (sFLC), but data on its impact on clinical outcome is limited and contradictory. To gain further insights we collected real world data from two major myeloma and nephrology centers in Austria and the Czech Republic. METHODS: Sixty-one patients with MM and acute kidney injury, who were treated between 2011 and 2019 with HCO hemodialysis and bortezomib-based MM therapy, were analyzed. RESULTS: The median number of HCO hemodialysis sessions was 11 (range 1-42). Median glomerular filtration rate at diagnosis was 7 ± 4.2 ml/min/1.73m2. sFLC after the first HCO hemodialysis decreased by 66.5% and by 89.2% at day 18. At 3 and 6 months, 26 (42.6%) and 30 (49.2%) of patients became dialysis-independent. CONCLUSION: The widely used strategy combining HCO hemodialysis and bortezomib-based antimyeloma treatment is dissatisfactory for half of the patients undergoing it and clearly in need of improvement.

Matrix Metalloproteinases and Their Tissue Inhibitors: an Evaluation of Novel Biomarkers in ANCA-Associated Vasculitis.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play an important role in both inflammation with subsequent fibrosis and in repair and healing in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We evaluated the circulating levels of MMPs, including pregnancy-associated plasma protein A (PAPP-A), and TIMPs in patients with AAV. PAPP-A, MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2 and selected parameters were measured in 100 AAV patients (36 patients with active disease and 64 patients in remission) and 34 healthy subjects. The levels of MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2, and PAPP-A in AAV were all found to be different to those of the controls. The MMP-7 and PAPP-A concentrations were increased in active disease in comparison to the controls (MMP-7: 13 ±.7 vs. 2 ± 0.6 ng/ml, PAPP-A: 14 ± 18 vs. 6.8 ± 2.6 ng/ml, both P < 0.005). The MMP-2 and TIMP-2 levels were increased in remission when compared to the controls (MMP-2: 242 ± 50 ng/ml vs. 212 ± 26 ng /ml, TIMP-2: 82 ± 14 ng/ml vs. 68 ± 93 ng/ml) and to the active AAV (MMP-2: 242 ± 50 vs. 219 ± 54 ng/ml, TIMP-2: 82 ± 14 ng/ml vs. 73 ± 15 ng/ml, all P < 0.005). MMP-3, MMP-7, TIMP-1, and PAPP-A correlated with serum creatinine. The serum levels of MMPs, TIMPs and PAPP-A are all altered in AAV. MMP-2, MMP-7 and TIMP-2 appear to be promising markers in distinguishing active AAV from remission. MMP-3, MMP-7, TIMP-1, and PAPP-A are associated with kidney function in AAV. Further studies are needed to delineate the exact roles of circulating MMPs, TIMPs and PAPP-A in patients with AAV.

Serum hepcidin is increased in ANCA-associated vasculitis and correlates with activity markers.

Hepcidin is a key regulator of iron metabolism and plays an important role in many pathologies. It is increased by iron administration and by inflammation, while erythropoiesis downregulates its expression. It decreases iron availability and thus contributes to anemia of chronic diseases. The aim of the study was to measure hepcidin as a marker and pathogenetic factor in ANCA-associated vasculitis (AAV). Hepcidin plasma concentration was measured by the immunological method in 59 patients with AAV and compared to patients with non-vasculitic etiology of chronic kidney disease, patients on hemodialysis (HD), with systemic lupus erythematodes (SLE) and to healthy controls and blood donors, and was correlated with the parameters of iron metabolism, inflammation, activity of the process and kidney function. Hepcidin concentration was increased in patients with AAV, SLE and HD and correlated positively with C-reactive protein, serum ferritin and creatinine, and negatively with hemoglobin and serum transferrin. In active form of AAV it correlated with the clinical scoring system (BVAS). Hepcidin can thus be considered as a pathogenetic factor of anemia in AAV and can be used for evaluation of inflammation in AAV and as an additional marker in active forms of the disease.

Toxocara spp. seronegativity in Czech patients with early form of multiple sclerosis - clinically isolated syndrome.

BACKGROUND: Helminth infections were reported to slightly modulate the host immune system response and decrease the risk of an autoimmune disorder, but on the other hand any infection may activate the immune system and trigger autoimmune reaction. In this study, we aimed to measure eosinophil levels and antibodies against Toxocara spp. in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). METHODS: In total, 220 CIS patients and 62 MS patients were examined. Antibodies against Toxocara secretory/excretory antigens (TES) were measured with an ELISA method. RESULTS: A total of 1,983 measurements of eosinophil levels were performed in CIS patients, out of which 95 results in 21 different patients were above the upper normal limit of the laboratory, but it was mostly only a relative increase. Two patients showed eosinophil levels above 20 % but both of them suffered from severe allergy. None of the CIS patients had any clinical signs of parasitic infections and the serological tests for antibodies against Toxocara were all negative. In all MS patients, eosinophil levels were in normal range. Antibodies against TES were detected in only 1 out of 62 (1.6%) MS patients. CONCLUSIONS: Based on our results it does not seem that Toxocara infection represents a potential trigger of MS. Nevertheless, our study indirectly confirms the hypothesis that parasitic infection may protect from autoimmunity.

Increased levels of soluble ST2 in patients with active newly diagnosed ANCA-associated vasculitis.

OBJECTIVE: ST2, a member of the interleukin-1 receptor family, is selectively expressed on Th2 cells and mediates important Th2 functions. IL-33 is a specific ligand of ST2. The aim of the study was to determine whether serum levels of soluble ST2 (sST2) or IL-33 predict activity of the disease in patients with ANCA-associated vasculitides (AAV). METHODS: 139 AAV patients and 62 controls were studied. IL-33 and sST2 in the blood were measured with a commercially available ELISA. RESULTS: Newly diagnosed AAV patients had higher sST2 levels than controls (P < 0.01). Levels of sST2 were significantly higher in active newly diagnosed AAV patients than in patients with remission (P < 0.001). IL-33 levels were higher in AAV patients than in the control groups (P = 0.002). However, serum IL-33 levels were not increased in patients with active AAV compared to patients in remission. IL-33 levels were higher in patients with granulomatosis with polyangiitis than in patients with microscopic polyangiitis (P = 0.012). CONCLUSIONS: Serum sST2, but not serum IL-33, may be a marker of activity in AAV patients.

Rituximab use in patients with ANCA-associated vasculitis: clinical efficacy and impact on immunological parameters.

Rituximab (RTX) was reported effective in ANCA-associated vasculitis (AAV). We aimed to evaluate clinical efficacy of RTX in AAV along with its impact on immunological parameters. Eighteen RTX-treated AAV patients (M/F 11/7; median age 37.5; 15× PR3-ANCA, 3× MPO-ANCA; 16× relapsing/refractory, 2× first-line therapy) were enrolled. Clinical response, ANCA, total serum IgG levels and cellular immunity parameters were examined. The patients were followed up (FU) for a median of 26 months (range 3-82, 15 for ≥6 months). All patients achieved B cell depletion (lasting 3-24 months). No significant increase was noted in T cell or NK cell subpopulations. At 6 months, partial remission was achieved in 5/15 patients (33 %) and complete in 8 (53 %). The median prednisone dose (30..10 mg/d) and ANCA levels (17.2..2.7 IU/mL) decreased (p < 0.01). RTX retreatment was used in nine (8× pre-emptive, 1× relapse). Six patients relapsed (none of the pre-emptively treated). Three patients died of infection. IgG levels at 3 months decreased compared to baseline (9.0 vs 5.7 g/L, p < 0.01). Higher percentage of HLA-DR+CD3+ cells and lower percentage of CD4+CD45RA+ naive T cells persisted during FU. IFN-γ production increased at 6 months compared to baseline (27.3 vs 41.5 %). No significant change was noted in the intracellular IL-10 and IL-12 production. RTX helped to lower the glucocorticosteroids dose and withdraw cytotoxic drugs in most AAV patients. Hypogammaglobulinaemia was common but well tolerated. Peripheral circulating T cells remained activated despite B cell depletion.

Long-term outcome of severe alveolar haemorrhage in ANCA-associated vasculitis: a retrospective cohort study.

OBJECTIVES: Alveolar haemorrhage (AH) is a major cause of early death in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). There is a paucity of information regarding the outcomes of AAV patients presenting with severe AH. METHOD: A retrospective cohort study. Patients with severe AH were identified from a case review of 824 AAV patients. Demography, presenting features, treatment, and outcomes are described. RESULTS: Fifty-three patients (33 males, 20 females; median age 59 years) with severe AH were identified: 37 (69.8%) with granulomatosis with polyangiitis (Wegener's) and 16 with microscopic polyangiitis [36 proteinase 3 (PR3)-ANCA positive and 17 myeloperoxidase (MPO)-ANCA positive]. AH was the first disease manifestation in 46 (86.8%) patients. Assisted ventilation was required in 36 (67.9%), renal involvement was present in 52 (98.1%), and 28 (52.8%) required dialysis. Forty (75.5%) received plasma exchange. At 3 months, 44/53 (83.0%) were alive. The mean follow-up was 49 months when 31 (58.5%) were alive and 24 (45.3%) dialysis independent. Mortality was higher in those requiring dialysis at entry (57.1% vs. 24%, p = 0.02) and in patients aged > 65 years (71.4% vs. 30.8%, p = 0.01), and tended to be higher in those requiring intubation (54.5% vs. 32.2%, p = 0.1). CONCLUSIONS: Severe AH was more commonly associated with PR3-ANCA (vs. MPO-ANCA) and strongly correlated with renal vasculitis. Current treatment of severe AH leads to remission but long-term mortality remains high. Concurrent renal failure and older age were associated with higher mortality.

Recent news in the treatment of lupus nephritis.

Patient survival and renal survival of patients with lupus nephritis improved, but still in a significant proportion of patients the disease progresses to end-stage renal failure, possibly at least partly due to slow and incomplete response to induction treatment and high relapse rate on the maintenance treatment. Mycophenolate mofetil was recently demonstrated to be a comparably effective and safe induction treatment of lupus nephritis as high-dose cyclophosphamide pulses, in Caucasian patients it has become a reasonable alternative to low-dose cyclophosphamide pulses according to the EUROLUPUS protocol. Mycophenolate was shown to be more effective than azathioprine in the maintenance treatment and is currently the treatment of choice for this phase of the disease. Rituximab should be reserved for patients refractory (or intolerant) to cyclophosphamide and/or mycophenolate. Therapy of lupus nephritis should be individually tailored; more aggressive therapy should be reserved for patients at high risk for renal dysfunction and its progression.

Novel flow cytometric method for the detection of podocalyxin-positive elements in urine of patients with glomerulonephritides - first promising results.

Glomerulonephritides together create a heterogenic group of supposedly immunologically mediated diseases of glomeruli. They still belong among the most frequent causes of chronic renal failure. Detection of podocytes in urine might serve as an important marker of glomerulonephritides activity. The aim of this study was to develop a novel flow cytometric method for the detection of podocyte fragments and podocytes in urine and assess its possible use in clinical practice. We placed emphasis on the improvement of pre-analytic phase. To suppress the autofluorescence of the background, blocking solutions and magnetic separation were used. An additional surface marker CD10 (nephrilysin) was used together with routinely used podocalyxin (PCX) in order to achieve better identification of podocytes. Based on the surface marker expression, three different element types were identified in the urine samples: PCX+/CD10+ elements (EL) (supposedly podocytes), PCX-/CD10+ EL (supposedly parietal epithelial cells) and PCX+ EL. We examined a total of 36 patients who underwent renal biopsy (non-glomerular nephropathy, MGN, FSGS, IgAN, AAV and MPGN) and 27 healthy controls. Negative results were found in non-glomerular nephropathy and in MGN. In patients with FSGS and IgAN, the levels of urine elements were slightly increased. The highest levels of all elements were found in AAV and MPGN. Our first results suggest that flow cytometric detection may distinguish between glomerular and nonglomerular diseases and that the levels of urine elements might correlate with the degree of glomerular destruction.

Can adequate treatment influence the postembolization syndrome and cytokine release in patients undergoing iatrogenic renal artery embolization?

The complete renal artery embolization is an alternative to surgical nephrectomy in seriously ill patients. Iatrogenic embolization can be used in many different conditions. Refractory nephrotic syndrome represents a very rare indication for embolization. Complete renal artery embolization has usually been complicated by postembolization syndrome (PES) which is characterized by flank pain and fever. Possible immunologic contribution to the PES leads some authors to the administration of corticosteroids to the patients undergoing embolization. We report here a cohort of 13 patients undergoing complete embolization of total 21 kidneys due to refractory nephrotic syndrome non-responding to the various specific treatment regimes. We treated our patients undergoing renal artery embolization according to special protocol containing combination of antibiotic drugs and corticosteroids (CS) to diminish PES and evaluated its influence to the cytokine production. The incidence of PES was less frequent and milder in comparison with the historical group of patients. Significant decrease in plasma levels of tumor necrosis factor α during first post-embolization day (8.37 pre- vs. 5.74 pg/ml post-embolization, P=0.0002) could partially explain the reduction of PES symptoms. The procedure was not complicated by severe complications and represents an elegant alternative to surgical procedure. The accurate timing of the embolization remains a controversial point in this intervention.

[Peritoneal dialysis and its modification in the treatment of chronic renal failure]. / Peritoneální dialýza a její modifikace v lécbe chronického selhání ledvin.

Three methods can be used to treat chronic renal failure - haemodialysis, peritoneal dialysis and renal transplantation (from a living donor or transplantation of a cadaver kidney). In 2009, 5,763 patients were treated with haemodialysis in the Czech Republic, while peritoneal dialysis was used in just 8% (458) of patients. This low number of peritoneal dialyses may be due to the still high number of chronic renal failure patients who come to dialysis centres "offthe street". Following acute initiation of haemodialysis, these patients are usually retained on haemodialysis. Poor awareness of peritoneal dialysis among patients as well as health care professionals is another reason for the low number of peritoneal dialysis patients. Peritoneal dialysis is suitable for home treatment. Peritoneum serves as the dialysis membrane, peritoneal cavity is filled with dialysis solution and the metabolism waste products and water are excreted into this solution. A base to correct metabolic acidosis then passes from dialysis solution into the body. Permanent catheter is inserted into the abdominal cavity to enable infusion of the dialysis solution. The dialysis is continual and this ensures stability of the inner environment and thus most closely resembles own kidney function. The advantages of peritoneal dialysis include longer preservation of residual renal function, inner environment stability and no need for venous access. Peritoneal dialysis is associated with a lower risk of infections. Peritoneal dialysis is contraindicated in patients after an extensive intraabdominal surgery and in patients with a stoma. Peritoneal damage is a serious complication of peritoneal dialysis; the risk increases with the treatment duration and thus peritoneal dialysis is not a long-term treatment choice. With the traditional CAPD (continual ambulatory peritoneal dialysis), the patient performs an exchange ofdialysis solution him/herself4 to 5 times a day. With APD (automated peritoneal dialysis) a machine performs dialysis solution exchanges, dialysis is performed at night and the patient may engage in other activities during a day. From the perspective of log-term survival of patients with chronic renal failure, peritoneal dialysis appears to be the method of choice. The patient is first treated with peritoneal dialysis and subsequently receives a transplant. Should the renal allograft be rejected, the patient returns to the dialysis programme, either peritoneal or haemodialysis. Patients should be provided with true and objective information about their disease and be informed about all treatment options for chronic renal failure. The choice of method has to be tailored to the overall health status of the patient as well as his/her lifestyle.

T cells in the pathogenesis of ANCA-associated vasculitis: current knowledge.

AAV are a group of systemic immune-mediated diseases with a strong and highly specific association with ANCA. In recent years, there has been increasing evidence that ANCA might play a direct pathogenic role in triggering AAV. Nevertheless, effectors of cell-mediated immunity prevail in the inflammation sites in patients with AAV. Numerous studies found increased markers of T-cell activation in AAV. Moreover, this activation persisted even in remission and despite treatment. Finally, successful therapeutic attempts using T cell-directed treatment were also reported. There has therefore been substantial evidence that T cells are involved in the pathogenesis of AAV, even though the exact mechanisms are yet to be elucidated. In this review, recent findings on the contribution of T cells to the pathogenic processes in AAV will be briefly summarized. Special emphasis will be placed on the Th1/Th2 concept, the role of T-regulatory cells, and the role of effector memory T cells in the pathogenesis of AAV.