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Background: Heart failure (HF) is a frequent cause of morbidity and mortality of end-stage kidney disease (ESKD) patients on hemodialysis. It is not easy to distinguish HF from water overload. The traditional HF definition has low sensitivity and specificity in this population. Moreover, many patients on hemodialysis have exercise limitations unrelated to HF. Therefore, we postulated two new HF definitions ((1) Modified definition of the Acute Dialysis Quality Improvement working group; (2) Hemodynamic definition based on the calculation of the effective cardiac output). We hypothesize that the newer definitions will better identify patients with higher number of endpoints and with more advanced structural heart disease.Methods: Cohort, observational, longitudinal study with recording predefined endpoints. Patients (n= 300) treated by hemodialysis in six collaborating centers will be examined centrally in a tertiary cardiovascular center every 6–12 months lifelong or till kidney transplantation by detailed expert echocardiography with the calculation of cardiac output, arteriovenous dialysis fistula flow volume calculation, bio-impedance, and basic laboratory analysis including NTproBNP. Effective cardiac output will be measured as the difference between measured total cardiac output and arteriovenous fistula flow volume and systemic vascular resistance will be also assessed non-invasively. In case of water overload during examination, dry weight adjustment will be recommended, and the patient invited for another examination within 6 weeks. A composite major endpoint will consist of (1) Cardiovascular death; (2) HF worsening/new diagnosis of; (3) Non-fatal myocardial infarction or stroke. The two newer HF definitions will be compared with the traditional one in terms of time to major endpoint analysis.Discussion: This trial will differ from others by: (1) detailed repeated hemodynamic assessment including arteriovenous access flow and (2) by careful assessment of adequate hydration to avoid confusion between HF and water overload.

There is a dearth of data characterizing patients receiving kidney replacement therapy (KRT) for kidney failure due to systemic lupus erythematosus (SLE) and their clinical outcomes. The aim of this study was to describe trends in incidence and prevalence of KRT among these patients as well as to compare their outcomes versus those of patients treated with KRT for diseases other than SLE.

The onset of IgA nephropathy (IgAN), characterized by glomerular deposition of IgA-containing immune complexes, is often associated with synpharyngitic hematuria. Innate immune responses mediated by Toll-like receptors (TLR) may play a role in IgAN onset and/or progression. Here, we assessed the expression of TLR 4, 7, 8, and 9 in renal-biopsy specimens from patients with IgAN, with different degree of proteinuria and eGFR, compared with normal-kidney and disease-control tissues (ANCA-associated vasculitis). Renal-biopsy specimens from 34 patients with IgAN and 7 patients with ANCA-associated vasculitis were used. In addition, we used 15 healthy portions of renal-tissue specimens from kidneys after nephrectomy for cancer as control specimens. Expression of TLR 4, 7, 8, and 9 was assessed using immunohistochemical staining of paraffin-embedded renal-biopsy tissue specimens with specific antibodies and evaluated semiquantitatively by light microscopy. Linear discriminant analysis (LDA) was used to test whether intrarenal staining of TLR 4, 7, 8, and 9 distinguished patients with IgAN from controls or correlated with eGFR and/or proteinuria. eGFR was calculated using the creatinine-based formula. Moreover, the biopsies from patients with IgAN were scored according to the Oxford Classification. LDA showed that staining for TLR 4, 7, 8, and 9 was more intense in specimens from IgAN patients compared to normal kidney tissues. The intensity of intrarenal staining of TLRs discriminated four groups of IgAN patients with different eGFR and proteinuria and MEST scoring.

Data for outcomes of patients with end-stage renal disease (ESRD) secondary to systemic sclerosis (scleroderma) requiring renal replacement therapy (RRT) are limited. We examined the incidence and prevalence of ESRD due to scleroderma in Europe and the outcomes among these patients following initiation of RRT.

ABSTRACTIntroduction: Treatment of systemic lupus erythematosus (SLE) represents a challenge due to variable disease manifestations, clinical course, and outcome. Long-term outcome in SLE remain unsatisfactory and a search for new therapeutic options is definitely warranted. Despite expectations, most clinical trials performed in SLE and lupus nephritis in the last decade did not reach primary outcome, and the only drug that has been licensed is belimumab.Areas covered: Results of negative trials testing monoclonal antibodies and other biologic agents in SLE are briefly summarized. Reasons for the failure of the trials are listed and discussed.Expert opinion: Future studies should recruit patients with similar organ involvement, better defined disease manifestations, higher activity, and similar severity. In addition to testing higher efficacy if given as add-on treatment to standard-of-care, the trials should be aimed at reducing dosing, or completely eliminating some parts of the current standard treatment, especially corticosteroids. Median follow-up of the patients should be longer. Moreover, specific biomarkers are needed to help to identify eligible patients and to better define response to treatment. An urgent unmet need is testing these new drugs in patients with severe SLE (including those refractory to current treatment).

ABSTRACTIntroduction: ANCA-associated vasculitis (AAV) is a rare but potentially life-threatening disease. Currently used induction treatment (cyclophosphamide or rituximab with high-dose corticosteroids) has significantly improved outcome of AAV, but is associated with high toxicity. Alternative complement pathway activation was shown to play a role in the pathogenesis of AAV, thus providing rationale for the use of avacopan, a selective inhibitor of C5a receptor, in the treatment of AAV.Areas covered: Pharmacokinetic and pharmocodynamic properties of avacopan, clinical efficacy and safety and tolerability of avacopan in so far performed clinical trials in patients with AAV are reviewed and discussed.Expert opinion: Avacopan was shown to have at least similar efficacy compared to high dose corticosteroids in patients with active AAV with renal involvement, while there were no major safety issues reported. Replacement of corticosteroids should decrease the corticosteroid-related toxicity and improve long-term outcome of patients with AAV even though this still needs to be confirmed in a larger trial. Data on long-term outcome of avacopan-treated patients are currently lacking and will be eagerly awaited. In the future, avacopan could replace corticosteroids not only in the induction phase, but also in the maintenance treatment of AAV.

ABSTRACTIntroduction: Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug licensed and approved by the US FDA and the European Medicines Agency (EMA) for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE).Areas covered: This manuscript evalues the recent data concerning belimumab’s safety and clinical effectiveness and its current place in the treatment of SLE. This includes an overview of the recent data coming from the post-hoc analyses of the BLISS trials, real-life experience with belimumab and the accumulating data on its safety. Attention is also paid to the progress made in the identification of predictors of response to belimumab, recent phase I/II/III studies with subcutaneous belimumab, and experience with B cell modulation coming from recent trials with other B cell modulating drugs.Expert opinion: Belimumab currently has its established role in the treatment of patients with SLE with serologic activity and clinical activity namely in mucocutaneous and musculoskeletal domains despite standard of care treatment. Better identification of patients who can benefit from treatment with belimumab is warranted. Data from ongoing studies in lupus nephritis and other data from observational studies are eagerly awaited.

Rituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking. We conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m2. We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events. A total 37 patients met the inclusion criteria. The median age was 61 years. (55–73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m2(7–16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200–1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m2. Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed. This study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.

Autoantibodies against monomeric C-reactive protein (anti-CRP-Ab) observed in patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) were suggested to be associated with active LN and a poor response to therapy during short-term follow-up. The aim of this study was to confirm this finding and to investigate the prognostic value of anti-CRP-Ab in patients with LN during long-term follow-up. Sera of 57 SLE patients (47 women, 10 men) with biopsy proven LN and 122 healthy individuals were analyzed for the presence of anti-CRP-Ab by in-house ELISA. Anti-CRP-Ab levels were studied in relation to routine laboratory tests, urine analysis, levels of C3, C4, other immunological markers and the overall disease activity as assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The prognostic value of anti-CRP-Ab was tested in a subgroup of 29 newly diagnosed LN patients (median follow-up 5.9 years). Response to therapy at various time points was assessed with respect to baseline anti-CRP-Ab levels. At least partial response in the first/second year of treatment was considered as a “favorable outcome”, while non-response, renal flare or end stage renal disease were considered as “unfavorable outcome”. Anti-CRP-Ab were only detected in patients with active renal disease and their levels correlated with SLEDAI (rs?=?0.165, p?=?0.002). The time to response was shorter in patients being anti-CRP-Ab negative at baseline compared to anti-CRP-Ab positive patients, p?=?0.037. In the second year of therapy, baseline anti-CRP-Ab positivity was a significant predictor of “unfavorable outcome” (OR [95 % CI]?=?15.6 [1.2-771]; p?=?0.021). The predictive value of “baseline anti-CRP positivity” further increased when combined with “non-response to therapy in the first year”. Baseline anti-CRP-Ab positivity was not a predictor of “unfavorable outcome” at the end of follow-up, (OR [95 % CI]?=?5.5 [0.6-71.1], p?=?0.169). Baseline serum levels of anti-CRP-Ab seem to be a strong risk factor for a composite outcome of non-response, renal flare or end stage renal disease after two years of standard treatment of LN. The response to therapy seems to be delayed in anti-CRP-Ab positive patients.

This study describes the incidence and outcomes of European patients requiring renal replacement therapy (RRT) for kidney failure due to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Background:Lupus nephritis (LN) is still associated with significant mortality and substantial risk of progression to end-stage renal failure. Its outcome is related to the class and severity of LN and response to treatment, and it is poorer in patients with renal relapses. Ethnicity has a relatively well-defined impact on the outcome of the patients and their response to treatment and must always be taken into consideration in treatment decisions. Summary:In this article, we provide a review of the impact of ethnicity on the prevalence of systemic lupus erythematosus (SLE), the proportion of patients with SLE developing LN, outcomes of SLE and LN and response of LN to treatment. In European patients, the prevalence of SLE and the proportion of SLE patients with LN are lower and the outcome of LN is better than in nonwhite populations. European patients may respond better to some modes of treatment [e.g. cyclophosphamide (CYC) or rituximab] and may be less frequently refractory to treatment compared to black patients with LN. Although these differences may be largely genetically driven, socioeconomic factors (poverty, education, insurance, access to health care and adherence to treatment) may also play a significant role in some disadvantaged patients. Key Message:Treatment of LN may be different in patients with different ethnicity. Less aggressive disease in European patients may better respond to less aggressive treatment. Treatment of LN in nonwhite patients may require newer (more effective) therapeutic approaches, but targeting negative socioeconomic factors might be even more effective. Facts from East and West:(1) The prevalence of SLE is lower among Caucasians than other ethnicities. A higher prevalence is observed among Asians and African Americans, while the highest prevalence is found in Caribbean people. The prevalence of LN in Asian SLE patients is much higher than in Caucasians as well. However, the 10-year renal outcome and renal survival rate appear to be better in Asians. (2) Polymorphisms of genes involved in the immune response, such as Fcγ receptor, integrin alpha M, TNF superfamily 4, myotubularin-related protein 3 and many others, might be partly responsible for the differences in prevalence between the different ethnic groups. European ancestry was shown to be associated with a decrease in the risk of LN even after adjustment for genes most associated with renal disease. (3) Access to health care is a key determinant of disease progression, treatment outcome and the management of complications such as infections, particularly in South Asia, and might also explain disparities between clinical outcomes. (4) The efficacy of low-dose CYC combined with corticosteroids for induction treatment of LN was proved in European Caucasian patients. This treatment is also used in Asia, although no formal evaluation of efficacy and safety in comparison with other treatment regimens exists in this population. The efficacy of mycophenolate mofetil (MMF) is similar to that of CYC, and similar between Asians and Caucasians. MMF may be more effective than CYC in inducing response in high-risk populations such as African American or Hispanic patients. MMF might cause less infection-related events in Asians, but its high cost prevents broader usage at present. (5) For maintenance therapy, corticosteroid combined with azathioprine (AZA) or MMF is used worldwide, with a broadly similar efficacy of both treatments, although there are data suggesting that in high-risk populations (e.g. African Americans) MMF may be more effective in preventing renal flares. AZA is often preferred in Asia due to economic constraints and because of its safety in pregnancy. (6) Alternative therapies under investigation include rituximab, which might be more efficient in Caucasians, as well as belimumab. Recent Japanese and Chinese studies have indicated a potential benefit of tacrolimus as a substitute for or in addition to CYC or MMF (dual or triple immunosuppression). Mizoribine is used in Japan exclusively.

Introduction:Antineutrophil cytoplasmic antibodies–associated vasculitis (AAV) is a group of autoimmune diseases characterized by the necrotizing inflammation of small vessels and associated with the antineutrophil cytoplasmic antibodies. Treatment of AAV can be divided into the induction phase aimed at achieving remission of the disease and the maintenance phase aimed at prevention of relapses. Long-term outcome of AAV dramatically improved with the introduction of cyclophosphamide. Recent clinical studies resulted in the reduction of the cumulative dose of cyclophosphamide and introduction of new treatment options, namely B-cell–depleting antibody rituximab, into both induction and maintenance treatment. This paper aims to evaluate the current role of the conventional induction and maintenance treatment in view of the gradually increasing use of rituximab.Areas covered:This paper provides an overview of the main clinical studies in induction and maintenance treatment of adult patients with AAV, treatment of relapses of AAV and shortly comments also on the treatment of refractory AAV, treatment of different subgroups of AAV (based on the age, renal function, clinical presentation and type of autoantibody), long-term outcome of patients with AAV, adverse events of treatment and treatment of end-stage renal disease in AAV.Expert opinion:Our analysis demonstrates that although the introduction of rituximab modified the approach to both the induction and maintenance treatment of AAV, more conventional induction and maintenance treatment with standard immunosuppressive drugs still retains its importance as we need more data on long-term efficacy and safety of biologic treatment, and also its cost-effectiveness still remains an open issue.

AbstractIntroduction of the standard immunosuppressive treatment has dramatically changed the outcome of patients with both ANCA-associated vasculitis and lupus nephritis, transforming them from incurable diseases with very high short-term mortality to chronic debilitating diseases with much lower short-term, but still relatively high long-term, morbidity/mortality. Long-term morbidity with damage accumulating partly due to the adverse events of the available treatment (namely gonadal toxicity, malignancy, bone disease, cataracts, diabetes, and thromboembolic and cardiovascular disease) has become a major concern. Although cyclophosphamide-based regimens have been partly replaced by newer agents in both ANCA-associated vasculitis and lupus nephritis (namely rituximab or mycophenolate, respectively) their short-term and medium-term adverse events may not be significantly less frequent and we can only hope that new treatments will translate into better long-term outcomes including better long-term safety.© 2014 S. Karger AG, Basel

Proliferative lupus nephritis is the most severe form of lupus nephritis. Outcomes of this disease are affected by ethnicity, clinical characteristics, irreversible damage on renal biopsy, initial response to treatment and future disease course (for example, the occurrence of renal flares). Initial intensive (induction) treatment of proliferative lupus nephritis is aimed at achieving remission, but optimal duration and intensity are not well defined. A combination of intravenous cyclophosphamide and corticosteroids have been shown to decrease the risk of end-stage renal disease, but are associated with substantial acute toxic effects (such as infections) and chronic toxic effects (such as ovarian failure). In white populations, low-dose cyclophosphamide is a reasonable alternative to high-dose cyclophosphamide as it is similarly effective and associated with less toxicity. Mycophenolate mofetil is as effective as high-dose intravenous cyclophosphamide in terms of inducing remission and similar in terms of safety. Although most patients respond to induction treatment, remission is often only achieved after patients are switched to maintenance treatment. As maintenance treatment, mycophenolate mofetil is superior to azathioprine and azathioprine is similarly effective to ciclosporin in terms of prevention or reducing the risk of relapse. Rituximab should be reserved for patients with refractory disease. Treatment of lupus nephritis should be individually tailored to patients, with more aggressive therapy reserved for patients at high risk of renal dysfunction and progression of renal disease.