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.

Sclerostin levels predict cardiovascular mortality in long-term hemodialysis patients: A prospective observational cohort study.

Sclerostin is a protein which is involved in bone metabolism and probably also in vessel wall function. This prospective observational cohort study evaluated the prognostic significance of sclerostin in hemodialysis (HD) patients. In total, 106 HD patients and 25 healthy controls participated in the study. HD patients were prospectively followed up for five years. Sclerostin was measured in serum using standard ELISA kits by Biomedica. Sclerostin concentrations in serum were higher in HD patients compared to the controls (89.2±40.3 pmol/l vs. 32.8±13.0 pmol/l, p<0.001). Sclerostin levels were significant for cardiovascular mortality but not for overall mortality and mortality due to infection. A higher cardiovascular risk was connected to sclerostin concentrations above the median (>84 pmol/l), HR (95 % CI): 2.577 (1.0002-10.207), p=0.04. When sclerostin was evaluated together with residual diuresis in Kaplan-Meier analysis the worst prognosis due to cardiovascular events was observed in the group with high sclerostin and zero residual diuresis compared to all other patients (p=0.007). In summary, serum sclerostin levels in HD patients were increased when compared to healthy subjects. High sclerostin levels were demonstrated as a risk factor for cardiovascular mortality. Further studies are required to clarify the pathophysiological mechanisms of sclerostin action in patients with renal failure before therapeutic measures can be established.

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.

Molecular profiling in IgA nephropathy and focal and segmental glomerulosclerosis.

The aim of the study was to characterize by molecular profiling two glomerular diseases: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) and to identify potential molecular markers of IgAN and FSGS progression. The expressions of 90 immune-related genes were compared in biopsies of patients with IgAN (n=33), FSGS (n=17) and in controls (n=11) using RT-qPCR. To identify markers of disease progression, gene expression was compared between progressors and non-progressors in 1 year follow-up. The results were verified on validation cohort of patients with IgAN (n=8) and in controls (n=6) using laser-capture microdissection, that enables to analyze gene expression separately for glomeruli and interstitium. In comparison to controls, patients with both IgAN and FSGS, had lower expression of BAX (apoptotic molecule BCL2-associated protein) and HMOX-1 (heme oxygenase 1) and higher expression of SELP (selectin P). Furthermore, in IgAN higher expression of PTPRC (protein-tyrosine phosphatase, receptor-type C) and in FSGS higher expression of BCL2L1 (regulator of apoptosis BCL2-like 1) and IL18 compared to control was observed. Validation of differentially expressed genes between IgAN and controls on another cohort using laser-capture microdissection confirmed higher expression of PTPRC in glomeruli of patients with IgAN. The risk of progression in IgAN was associated with higher expression EDN1 (endothelin 1) (AUC=0.77) and FASLG (Fas ligand) (AUC=0.82) and lower expression of VEGF (vascular endothelial growth factor) (AUC=0.8) and in FSGS with lower expression of CCL19 (chemokine (C-C motif) ligand 19) (AUC=0.86). Higher expression of EDN1 and FASLG along with lower expression of VEGF in IgAN and lower expression of CCL19 in FSGS at the time of biopsy can help to identify patients at risk of future disease progression.

Proteomic approach for identification of IgA nephropathy-related biomarkers in urine.

Proteinuria is often used as a surrogate marker in monitoring and predicting outcome in patients with chronic kidney diseases, but it is non-specific. IgAN belongs to the most common primary glomerulonephritis worldwide with serious prognosis. The main aim of this work was to assess differences in urine proteins in patients with IgA nephropathy and to identify abnormal proteins as potential biomarkers of IgA nephropathy or the renal disease. In our pilot project, we selected 20 patients and compared them with 20 healthy volunteers. Protein quantification was performed using iTRAQ (isobaric tag for relative and absolute quantitation) labeling method. The peptides were separated by the isoelectric focusing method (IEF) and nano-LC with C18 column and identified by mass spectrometry using MALDI-TOF/TOF MS. Proteins´ lists obtained from IEF-LC-MS-MS/MS analysis were combined and contained 201 proteins. It was found out that 113 proteins were common in both experiments. 30 urinary proteins were significantly up- or down-regulated in patients with IgA nephropathy. We characterized potential biomarkers such as alpha-1-antitrypsin, apolipoprotein A-I, CD44 antigen or kininogen. Potential biomarkers of IgAN should be validated in further studies.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

Genome-wide methylation analysis of tubulocystic and papillary renal cell carcinomas.

Tubulocystic renal cell carcinoma (TRCC) represents a rare tumor with incidence lower than 1 % of all renal carcinomas. This study was undertaken to contribute to characterization of molecular signatures associated with TRCC and to compare them with the features of papillary renal cell carcinoma (PRCC) at the level of genome wide methylation analysis.We performed methylated DNA immunoprecipitation (MeDIP) coupled with microarray analysis (Roche NimbleGen). Using the CHARM package, we compared the levels of gene methylation between paired samples of tumors and control renal tissues of each examined individual. We found significant global demethylation in all tumor samples in comparison with adjacent kidney tissues of normal histological appearance but no significant differences in gene methylation between the both compared tumor entities. Therefore we focused on characterization of differentially methylated regions between both tumors and control tissues. We found 42 differentially methylated genes.Hypermethylated genes for protocadherins (PCDHG) and genes coding for products associated with functions of plasma membrane were evaluated as significantly overrepresented among hypermethylated genes detected in both types of renal cell carcinomas.In our pilot study, we provide the first evidence that identical features in the process of carcinogenesis leading to TRCC and/or to PRCC may be found at the gene methylation level.

Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts.

OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.

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.

Extended follow-up of the CYCLOFA-LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A.

Objective To evaluate the extended follow-up of the CYCLOFA-LUNE trial, a randomized prospective trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide (CPH) or cyclosporine A (CyA). Patients and methods Data for kidney function and adverse events were collected by a cross-sectional survey for 38 of 40 patients initially randomized in the CYCLOFA-LUNE trial. Results The median follow-up time was 7.7 years (range 5.0-10.3). Rates of renal impairment and end-stage renal disease, adverse events (death, cardiovascular event, tumor, premature menopause) did not differ between the CPH and CyA group, nor did mean serum creatinine, 24 h proteinuria and SLICC damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. Conclusion An immunosuppressive regimen based on CyA achieved similar clinical results to that based on CPH in the very long term.

Endotelial activation and flow-mediated vasodilation in young patients with breast cancer.

Endothelial activation and dysfunction may play a significant role in the progression of breast cancer. In our study we examined markers of endothelial activation (soluble ICAM-1, P-selectin, E-selectin) in 98 young patients with breast cancer (< 40 years). In 50 of them (and 20 age-matched controls) we also measured flow mediated vasodilation. Patients with breast cancer had significantly higher serum levels of soluble E-selectin, P-selectin and ICAM-1, P-selectin was higher in patients with larger tumors, node involvement and seemed to be apredictor of poor outcome. We were unable to find significant difference in the parameters of flow mediated vasodilation between patients with breast cancer and healthy subjects, although both peak blood flow (PBF) and flow mediated vasodilation (FMD) seemed to be skewed compared to healthy subjects toward mean and lower levels. Cluster analysis enabled us to distinguish several larger groups of patients with different degree of endothelial activation and function and different outcome. Group of patients with high E-selectin, high ICAM-1 (higher endothelial activation) and low VEGF (putative endothelial damage) had more frequently negative estrogen receptors and had worse outcome compared to the group of patients with lower E-selectin, lower ICAM-1 and mostly positive estrogen receptors. Further studies of larger groups of patients should help to identify the panel of endothelial markers which could help in predicting the outcome of young patients with breast cancer.

[Hypertension in patients with polycystic kidney disease -  incidence, pathogenesis, prognosis, therapy]. / Hypertenze u pacientu s polycystickými ledvinami -  incidence, patogeneze, prognóza, terapie.

Hypertension is common in patients with autosomal dominant polycystic kidney disease (ADPKD) very early usually already in adolescence and its occurrence precedes the decrease of glomerular filtration rate. Expansion of renal cysts causing local renal ischemia and activation of the reninangiotensin system is believed to play a decisive role in its pathogenesis. Hypertension in ADPKD leads to early development of left ventricle hypertrophy and definitely contributes to the progression of chronic renal insufficiency. In ADPKD optimal control of blood pressure dramatically decreases the risk of left ventricle hypertrophy and contributes to its regression, but the beneficial effect of optimal compared to standard blood pressure control on the progression of chronic renal insufficiency has yet to be unequivocally demonstrated. Angiotensin converting enzyme inhibitors and/ or angiotensin receptor blockers are the drugs of choice in the treatment of hypertension in ADPKD. New drugs blocking the growth of renal cysts (e. g. inhibitors of V2 vasopressin antagonists) may have in ADPKD positive impact not only of the growth of the cysts and kidney volume, but also on the rate of loss of glomerular filtration rate. The influence of these drugs on the control of blood pressure, if any, remains uncertain.

Mutational analysis of ACTN4, encoding α-actinin 4, in patients with focal segmental glomerulosclerosis using HRM method.

α-Actinin 4, encoded by ACTN4, is an F-actin crosslinking protein which belongs to the spectrin gene superfamily. It has a head-to-tail homodimer structure with three main domains. Mutations in ACTN4 are associated with idiopathic nephrotic syndrome (NS). However, until today only a few mutations have been described in this gene. We used genomic DNA of 48 patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) to screen for ACTN4 mutations by high-resolution melting analysis (HRM). Suspect samples were sequenced and compared with healthy controls. To investigate the prevalence and possible effect of some substitutions found in FSGS/MCD patients we also looked for these changes in patients with IgA nephropathy (IgAN) and membranous glomerulonephritis (MGN). We found 20 exonic and intronic substitutions in the group of 48 Czech patients. The substitution 2242A>G (p.Asn748Asp) is a candidate mutation which was identified in one patient but not in any of the 200 healthy controls. Exon 19 seems to be a variable region due to the amount of revealed polymorphisms. In this region we also found three unreported substitutions in IgAN patients, c.2351C>T (p.Ala784Val), c.2378G>A (p.Cys793Tyr) and c.2393G>A (p.Gly798Asp). These substitutions were not found in any tested healthy controls. To conclude, the ACTN4 mutations are not a frequent cause of FSGS/MCD in Czech adult patients. One new ACTN4 mutation has been identified.

Recent insights into the pathogenesis of nephrotic syndrome.

Nephrotic syndrome is characterized by heavy proteinuria followed by hypoproteinemia, hypercholestrolemia, lipiduria, and edema. The glomerular filtration barrier (GFB) consists of glomerular endothelial cells covered with glycocalyx, the basement membrane, subpodocyte space and podocytes with foot processes and slit membranes between them. The coordinated function of GFB has been considered to be the major barrier against filtration of plasma proteins to urine. However, new hypothesis suggesting more permeable GFB has emerged. According to this, proteinuria might be prevented by tubular protein reabsorbtion. Experiments and human studies have revealed numerous putative permeability factors in idiopathic nephrotic syndrome (minimal change disease/focal segmental glomerulosclerosis). New antigens and antibodies have been suggested in "idiopathic" membranous nephropathy as well. Formation of nephrotic edema, the role of oncotic pressure and of different sodium and water retaining hormones have been subject of intensive study. These findings should pave the way to new therapeutic modalities targeted more precisely to the pathogenic mechanisms.

Proteinuria and hypertension in patients treated with inhibitors of the VEGF signalling pathway--incidence, mechanisms and management.

Anti-VEGF therapy dramatically improved the outcome of patients with renal cancer and other advanced malignancies, but may be complicated by proteinuria and hypertension. VEGF is indispensable for the normal development of glomerulus and preservation of glomerular filtration barrier. Interference with its action may result in damage to glomerular endothelial cells and (in severe cases) in renal thrombotic microangiopathy. Blood pressure and proteinuria (using dipstick) should be assessed in all patients before starting anti-VEGF therapy and regularly monitored during the treatment. Patients with severe proteinuria and/or impaired renal function should be referred to the nephrologist for further work-up. Hypertension caused by anti-VEGF therapy can be effectively treated; progression of proteinuria and/or renal dysfunction may require tapering, or even withdrawal of anti-VEGF treatment.

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.

TRPC6 gene variants in Czech adult patients with focal segmental glomerulosclerosis and minimal change disease.

Blood filtration and formation of primary urine in the kidney glomerulus is provided by a specialized membrane called slit diaphragm located between well-branched pedicels of podocytes. Actually, the slit diaphragm is a protein supercomplex, whose disruption can cause failure of renal filtration, and patients usually manifest nephrotic syndrome. Recently, familial forms of nephrotic syndrome have been described which arise from malfunction of mutated proteins making up the slit diaphragm. In 2005 it was found that one of the proteins present in this complex was non-selective cation channel TRPC6. The aim of this work was to screen mutations and polymorphisms of the TRPC6 gene in a group of 64 Czech patients with nephrotic syndrome and subsequently, on the basis of these data, evaluate the role of mutations in the TRPC6 gene in Czech population. The analysis was performed by the PCR method followed by direct sequencing and high-resolution melting method. We have not identified any mutations in our group of patients. Two additional single nucleotide polymorphisms - p.P15S and p.A404V - were detected along with nucleotide changes that did not result in amino acid changes and with a few intronic changes. P.P15S heterozygotes were more frequent in patients with steroid-resistant FSGS than in steroid- sensitive patients (29 % versus 12.1 %). To conclude, we did not find any probable disease-causing mutation in the TRPC6 gene in the cohort of 64 Czech patients. The p.P15S polymorphism might have some influence on the therapeutic response of FSGS patients.

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.